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McLarnon SR, Honeycutt SE, N'Guetta PEY, Xiong Y, Li X, Abe K, Kitai H, Souma T, O'Brien LL. Altered renal vascular patterning reduces ischemic kidney injury and limits age-associated vascular loss. Am J Physiol Renal Physiol 2025; 328:F876-F889. [PMID: 40331791 DOI: 10.1152/ajprenal.00284.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/05/2024] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular pattern is dependent on netrin-1 secreted by renal stromal progenitors. Mice lacking netrin-1 (Ntn1) from these cells develop an arterial tree with stochastic branching, particularly of the large interlobar vessels. The current study investigated whether abnormalities in renal vascular patterning altered kidney function or response to injury. To examine this, we analyzed kidney function at baseline as well as in response to a model of bilateral ischemic injury and measured vascular dynamics in 7- to 8-mo-old mice. We found no differences in kidney function or morphology at baseline between mice with an abnormal arterial pattern compared with control. Interestingly, male and female mutant mice with stochastic vascular patterning showed a reduction in tubular injury in response to ischemia. Similarly, mutant mice also had a preservation of perfused vasculature with increased age compared with a reduction in the control group. These results suggest that guided and organized patterning of the renal vasculature may not be required for normal kidney function, but uncovers new implications for patterning in response to injury. Understanding how patterning and maturation of the arterial tree affects physiology and response to injury has important implications for enhancing kidney regeneration and tissue engineering strategies.NEW & NOTEWORTHY Kidney vascular patterning is established through responses to guidance cues such as netrin-1; however, the significance of proper patterning to function and injury response remains unexplored. Here, utilizing a conditional knockout of netrin-1 (Ntn1) that displays persistent abnormal arterial patterning, we identify no significant disruptions to normal kidney physiology in adult animals but, surprisingly, less tubular damage in response to ischemic injury. This study uncovers new and significant implications for proper kidney vascular patterning.
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Affiliation(s)
- Sarah R McLarnon
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Samuel E Honeycutt
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Pierre-Emmanuel Y N'Guetta
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Yubin Xiong
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Xinwei Li
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Koki Abe
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States
| | - Hiroki Kitai
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States
| | - Tomokazu Souma
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States
- Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, United States
| | - Lori L O'Brien
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
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Ma K, Fujino M, Yang Y, Ding Z, Hu X, Ito H, Takahashi K, Nakajima M, Isaka Y, Li XK. 5-aminolaevulinic acid with sodium ferrous citrate alleviated kidney injury and fibrosis in a unilateral ureteral obstruction model. Int Immunopharmacol 2025; 150:114321. [PMID: 39970714 DOI: 10.1016/j.intimp.2025.114321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
PURPOSE This study aimed to investigate the potential therapeutic effects of 5-aminolaevulinic acid (5-ALA) combined with sodium ferrous citrate (SFC) on kidney injury and fibrosis in a mouse model of unilateral ureteral obstruction (UUO)-induced chronic kidney disease (CKD). METHODS A murine UUO model was used to mimic human CKD. The mice received daily intragastric administration of 5-ALA/SFC for 7 and 14 consecutive days. Serum creatinine (Cr) and blood urea nitrogen (BUN) levels and histological evaluations were performed to assess the renal function parameters underlying 5-ALA/SFC treatment in the UUO model. Differentially expressed genes (DEGs) were analyzed by RNA sequencing (RNA-Seq), and the results were validated by quantitative real-time PCR (qRT-PCR). The severity of renal fibrosis was evaluated using Sirius red and Masson's trichrome (MT) staining techniques, while the expression of fibrosis-related genes was examined using western blotting and immunohistochemistry. RESULTS Our findings demonstrated that 5-ALA/SFC treatment improved UUO-induced renal dysfunction, attenuated tubular damage, and significantly reduced serum Cr and BUN levels as well as the mRNA expression and secretion of pro-inflammatory and programmed cell death-related cytokines in kidney tissues. Furthermore, 5-ALA/SFC suppressed renal tissue fibrosis and downregulated the mRNA and protein expression of fibrosis-related genes. Notably, treatment with 5-ALA/SFC led to the significant upregulation of protein expression levels of PPAR gamma-coactivator-1α (PGC-1α), indicating its role in inhibiting inflammation and fibrosis through the activation of the PGC-1α signaling pathway. CONCLUSION 5-ALA/SFC exhibits renoprotective effects in UUO-induced CKD by attenuating inflammation, cell death, and suppressing renal fibrosis. These findings suggest a specific renal protective mechanism for 5-ALA/SFC, highlighting its potential as a novel therapeutic agent for human CKD treatment.
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Affiliation(s)
- Kuai Ma
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Nephrology, Osaka University Graduate School of Medicine, Japan
| | - Masayuki Fujino
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Research Center for Biosafety, Laboratory Animal and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan.
| | - Yang Yang
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Zhaolun Ding
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Xin Hu
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | | | | | | | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine, Japan.
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
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Kapitsinou PP. Metabolic Breakdown: The Hidden Role of Endothelial Glycolysis in Kidney Fibrosis. J Am Soc Nephrol 2025; 36:1-3. [PMID: 39602365 PMCID: PMC11706547 DOI: 10.1681/asn.0000000568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
Affiliation(s)
- Pinelopi P Kapitsinou
- Feinberg Cardiovascular & Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Xu C, Pan K, Li J, Li Y, Jin S, Shi Y, Teng J, Ding X, Xu X, Liu H. Serum soluble interleukin-2 receptor alpha may predict tubulointerstitial inflammatory cell infiltration and short-term disease progression in immunoglobin A nephropathy. Immunol Res 2024; 72:1350-1364. [PMID: 39276201 PMCID: PMC11618199 DOI: 10.1007/s12026-024-09533-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/24/2024] [Indexed: 09/16/2024]
Abstract
This study aims to explore the relationship between serum soluble interleukin-2 receptor alpha (sIL-2Rα) levels and histologic features in immunoglobin A nephropathy (IgAN), and evaluate its predicting values on disease progression and remission status. IgAN patients were included retrospectively. Lee classification, Oxford classification and histological scoring were evaluated. Patients' estimated filtration rate (eGFR) and proteinuria remission status were collected during 6-month follow-up. Logistic regression was used to determine the risk factors and predicting value. Receiver operating characteristic (ROC) curve were used to determine the predicting value for outcome. One hundred seventy-two subjects were included in this study. Individuals in moderate-to-severe tubulointerstitial inflammatory cell infiltration group manifested with significantly elevated serum sIL-2Rα levels than those in non-to-mild group. Serum sIL-2Rα levels were positively correlated with infiltration scores. Serum sIL-2Rα was an independent risk factor for moderate-to-severe inflammatory cell infiltration [sIL-2Rα: OR 1.29 (1.015-1.640, p = 0.038)]. ROC curve analysis regarding predictive value for moderate-to-severe inflammatory cell infiltration of sIL-2Rα suggested area under curve was 0.859 (0.801-0.918, p = 0.000) when sIL-2Rα combined with eGFR < 60 mL/(min·1.73 m2), 24-h proteinuria excretion > 1.0 g, and hemoglobin. It showed good sensitivity (71.6%) and specificity (87.6%). Additionally, sIL-2Rα levels at kidney biopsy were strong predictive factor for kidney function loss 6 months after kidney biopsy [OR 4.161 (1.013-17.088, p = 0.048)]. High serum sIL-2Rα was significantly associated with serious inflammatory cell infiltration in IgAN, and it showed strong predictive value for disease prognosis. Serum sIL-2Rα could be a useful noninvasive biomarker to evaluate the extent of histological injury and disease prognosis in IgAN.
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Affiliation(s)
- Chenqi Xu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Institute of Kidney and Dialysis, Shanghai, 200032, China
| | - Kunming Pan
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jie Li
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Institute of Kidney and Dialysis, Shanghai, 200032, China
| | - Yang Li
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Institute of Kidney and Dialysis, Shanghai, 200032, China
| | - Shi Jin
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Institute of Kidney and Dialysis, Shanghai, 200032, China
| | - Yiqin Shi
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Institute of Kidney and Dialysis, Shanghai, 200032, China
| | - Jie Teng
- Department of Nephrology, Zhongshan Hospital (Xiamen), Fudan University, Nephrology Clinical Quality Control Center of Xiamen, Xiamen, 361015, China
| | - Xiaoqiang Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney Disease and Blood Purification, Shanghai Institute of Kidney and Dialysis, Hemodialysis Quality Control Center of Shanghai, Shanghai, 200032, China
| | - Xialian Xu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Institute of Kidney and Dialysis, Shanghai, 200032, China.
| | - Hong Liu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney Disease, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Institute of Kidney and Dialysis, Shanghai, 200032, China.
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Malvica S, Fenaroli P, Lee CY, Louis S, Celia AI, Bagnasco S, Yang X, Hodgin JB, Buyon J, Magder L, Petri M, Rosenberg A, Fava A. Inflammation in Areas of Fibrosis Precedes Loss of Kidney Function in Lupus Nephritis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.25.625225. [PMID: 39651286 PMCID: PMC11623599 DOI: 10.1101/2024.11.25.625225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Background Interstitial fibrosis in lupus nephritis (LN) is often infiltrated by immune cells but typically regarded as nonspecific "scar reaction." This study aimed to investigate the relationship between inflammatory fibrosis and kidney disease progression in LN. Methods Interstitial fibrosis and tubular atrophy (IFTA) were scored in 124 LN kidney biopsies. Inflammation in areas of IFTA (i-IFTA) was graded 0-3 according to the Banff Classification of Allograft Pathology. Significant glomerular filtration rate (GFR) loss was defined as a decline of >15 ml/min at 3 years from biopsy. Immune cell phenotype was defined by serial immunohistochemistry (13-plex). Results IFTA was observed in 88/124 (71%) biopsies, and i-IFTA was identified in 76/88 (86%) cases. The distribution of i-IFTA grades was heterogenous across all IFTA grades. In patients with moderate-to-severe IFTA (>25%), the degree of i-IFTA was associated with a higher risk of significant GFR loss: 0/2 (0%), 1/3 (33%), 3/4 (75%), and 7/9 (78%) for i-IFTA grades 0, 1, 2, and 3, respectively (p = 0.028). Multiplexed histology revealed that i-IFTA was mostly composed of CD163+ macrophages and CD4 T cells, followed by CD8 T cells and granulocytes. Conclusion I-IFTA is frequently observed in LN and is dominated by macrophages and T cells. For patients with baseline IFTA >25%, the degree of i-IFTA emerged as a predictor of GFR loss. These data support the routine scoring of i-IFTA in LN due to its prognostic implications and nominate i-IFTA as a potential therapeutic target. LAY SUMMARY Scar tissue often contains immune cells, but we still do not fully understand their role. In lupus nephritis (LN), this is typically dismissed as "nonspecific inflammation". However, our study analyzed kidney biopsies from 124 people with LN and found that inflammation in scarred areas may predict future kidney function loss. Specifically, we identified a type of immune cell, CD163+ macrophages, that may contribute to scarring and kidney damage. Our findings suggest that routinely assessing inflammation in scarred areas could help predict kidney health in LN patients and highlight a possible new target for therapies to prevent kidney damage.
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McLarnon SR, Honeycutt SE, N’Guetta PEY, Xiong Y, Li X, Abe K, Kitai H, Souma T, O’Brien LL. Altered renal vascular patterning reduces ischemic kidney injury and limits vascular loss associated with aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.29.620969. [PMID: 39553980 PMCID: PMC11565873 DOI: 10.1101/2024.10.29.620969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular pattern is dependent on netrin-1 secreted by renal stromal progenitors. Mice lacking netrin-1 develop an arterial tree with stochastic branching, particularly of the large interlobar vessels. The current study investigated whether abnormalities in renal vascular pattern altered kidney function or response to injury. To examine this, we analyzed kidney function at baseline as well as in response to recovery from a model of bilateral ischemic injury and measured vascular dynamics in aged mice. We found no differences in kidney function or morphology at baseline between mice with an abnormal arterial pattern compared to control. Interestingly, male and female mutant mice with stochastic vascular patterning showed a reduction in tubular injury in response to ischemia. Similarly, mutant mice also had a preservation of perfused vasculature with aging compared to a reduction in the control group. These results suggest that guided and organized patterning of the renal vasculature may not be required for normal kidney function; thus, modulating renal vascular patterning may represent an effective therapeutic strategy. Understanding how patterning and maturation of the arterial tree affects physiology and response to injury or aging has important implications for enhancing kidney regeneration and tissue engineering strategies.
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Affiliation(s)
- Sarah R. McLarnon
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Samuel E. Honeycutt
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Pierre-Emmanuel Y. N’Guetta
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yubin Xiong
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Xinwei Li
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Cell and Developmental Biology, Rutgers University, Piscataway, NJ 08854, USA
| | - Koki Abe
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hiroki Kitai
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Tomokazu Souma
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Lori L. O’Brien
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
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Cliff CL, Squires PE, Hills CE. Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease. Cell Commun Signal 2024; 22:351. [PMID: 38970061 PMCID: PMC11225428 DOI: 10.1186/s12964-024-01728-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/26/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Accompanied by activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, aberrant connexin 43 (Cx43) hemichannel-mediated ATP release is situated upstream of inflammasome assembly and inflammation and contributes to multiple secondary complications of diabetes and associated cardiometabolic comorbidities. Evidence suggests there may be a link between Cx43 hemichannel activity and inflammation in the diabetic kidney. The consequences of blocking tubular Cx43 hemichannel-mediated ATP release in priming/activation of the NLRP3 inflammasome in a model of diabetic kidney disease (DKD) was investigated. We examined downstream markers of inflammation and the proinflammatory and chemoattractant role of the tubular secretome on macrophage recruitment and activation. METHODS Analysis of human transcriptomic data from the Nephroseq repository correlated gene expression to renal function in DKD. Primary human renal proximal tubule epithelial cells (RPTECs) and monocyte-derived macrophages (MDMs) were cultured in high glucose and inflammatory cytokines as a model of DKD to assess Cx43 hemichannel activity, NLRP3 inflammasome activation and epithelial-to-macrophage paracrine-mediated crosstalk. Tonabersat assessed a role for Cx43 hemichannels. RESULTS Transcriptomic analysis from renal biopsies of patients with DKD showed that increased Cx43 and NLRP3 expression correlated with declining glomerular filtration rate (GFR) and increased proteinuria. In vitro, Tonabersat blocked glucose/cytokine-dependant increases in Cx43 hemichannel-mediated ATP release and reduced expression of inflammatory markers and NLRP3 inflammasome activation in RPTECs. We observed a reciprocal relationship in which NLRP3 activity exacerbated increased Cx43 expression and hemichannel-mediated ATP release, events driven by nuclear factor kappa-B (NFκB)-mediated priming and Cx43 hemichannel opening, changes blocked by Tonabersat. Conditioned media (CM) from RPTECs treated with high glucose/cytokines increased expression of inflammatory markers in MDMs, an effect reduced when macrophages were pre-treated with Tonabersat. Co-culture using conditioned media from Tonabersat-treated RPTECs dampened macrophage inflammatory marker expression and reduced macrophage migration. CONCLUSION Using a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes.
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Affiliation(s)
- C L Cliff
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK
| | - P E Squires
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK
| | - C E Hills
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK.
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Sun C, Wu X, Zhang X, Li S, Jia R, Sun D. Clinical efficacy of beraprost sodium in treating chronic kidney disease: A six-month prospective study. Heliyon 2024; 10:e24156. [PMID: 38293352 PMCID: PMC10825420 DOI: 10.1016/j.heliyon.2024.e24156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 11/19/2023] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Objective To investigate the clinical efficacy of beraprost sodium (BPS) in the treatment of chronic kidney disease (CKD). Methods In this single-centre, prospective, controlled, single-blind study, 252 patients diagnosed with CKD and treated at the Affiliated Hospital of Xuzhou Medical University were enrolled from September 2018 to June 2021. All participants were randomised into three groups: the control, BPS 40 μg, and BPS 20 μg groups. Both treatment groups were administered conventional therapy for 6 months. Renal function in the three groups was measured and compared 3 and 6 months post-treatment. Results 1. Renal function in the BPS 20 μg and BPS 40 μg groups was better than that in the control group after 3 and 6 months of treatment. 2. After 3 months of treatment, the levels of serum creatinine (P = 0.043), cystatin C (P = 0.039), and 24 h urinary total protein (P = 0.041) in the BPS 40 μg group were significantly lower than those in the BPS 20 μg group, the eGFR (P = 0.046) level was higher than that in the BPS 20 μg group, and the index improvement rate was better than that in the BPS 20 μg group (P < 0.05). 3. After 6 months of treatment, the improvement in renal function in the BPS 20 μg group was close to that in the BPS 40 μg group (P > 0.05). Conclusion BPS improved renal function, reduced urinary protein levels, and delayed CKD progression. The clinical efficacy of BPS in the 40 μg group was faster than that in the BPS 20 μg group. The long-term use of BPS is effective in patients with CKD.
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Affiliation(s)
- Chen Sun
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
- Department of Nephrology, Xuzhou Central Hospital, Xuzhou, 221009, China
| | - Xin Wu
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Xin Zhang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Shulin Li
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
- Institute of Nephrology, Xuzhou Medical University, Xuzhou, 221002, China
| | - Ruoyu Jia
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Dong Sun
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
- Institute of Nephrology, Xuzhou Medical University, Xuzhou, 221002, China
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Chang LY, Chao YL, Chiu CC, Chen PL, Lin HYH. Mitochondrial Signaling, the Mechanisms of AKI-to-CKD Transition and Potential Treatment Targets. Int J Mol Sci 2024; 25:1518. [PMID: 38338797 PMCID: PMC10855342 DOI: 10.3390/ijms25031518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/14/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.
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Affiliation(s)
- Li-Yun Chang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (L.-Y.C.); (Y.-L.C.)
| | - Yu-Lin Chao
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (L.-Y.C.); (Y.-L.C.)
| | - Chien-Chih Chiu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Phang-Lang Chen
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697, USA;
| | - Hugo Y.-H. Lin
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (L.-Y.C.); (Y.-L.C.)
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Khan MAH, Nolan B, Stavniichuk A, Merk D, Imig JD. Dual soluble epoxide hydrolase inhibitor - farnesoid X receptor agonist interventional treatment attenuates renal inflammation and fibrosis. Front Immunol 2024; 14:1269261. [PMID: 38235144 PMCID: PMC10791967 DOI: 10.3389/fimmu.2023.1269261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 12/12/2023] [Indexed: 01/19/2024] Open
Abstract
Introduction Renal fibrosis associated with inflammation is a critical pathophysiological event in chronic kidney disease (CKD). We have developed DM509 which acts concurrently as a farnesoid X receptor agonist and a soluble epoxide hydrolase inhibitor and investigated DM509 efficacy as an interventional treatment using the unilateral ureteral obstruction (UUO) mouse model. Methods Male mice went through either UUO or sham surgery. Interventional DM509 treatment (10mg/kg/d) was started three days after UUO induction and continued for 7 days. Plasma and kidney tissue were collected at the end of the experimental protocol. Results UUO mice demonstrated marked renal fibrosis with higher kidney hydroxyproline content and collagen positive area. Interventional DM509 treatment reduced hydroxyproline content by 41% and collagen positive area by 65%. Renal inflammation was evident in UUO mice with elevated MCP-1, CD45-positive immune cell positive infiltration, and profibrotic inflammatory gene expression. DM509 treatment reduced renal inflammation in UUO mice. Renal fibrosis in UUO was associated with epithelial-to-mesenchymal transition (EMT) and DM509 treatment reduced EMT. UUO mice also had tubular epithelial barrier injury with increased renal KIM-1, NGAL expression. DM509 reduced tubular injury markers by 25-50% and maintained tubular epithelial integrity in UUO mice. Vascular inflammation was evident in UUO mice with 9 to 20-fold higher ICAM and VCAM gene expression which was reduced by 40-50% with DM509 treatment. Peritubular vascular density was reduced by 35% in UUO mice and DM509 prevented vascular loss. Discussion Interventional treatment with DM509 reduced renal fibrosis and inflammation in UUO mice demonstrating that DM509 is a promising drug that combats renal epithelial and vascular pathological events associated with progression of CKD.
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Affiliation(s)
- Md. Abdul Hye Khan
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Benjamin Nolan
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Anna Stavniichuk
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Daniel Merk
- Department of Pharmacy, Ludwig-Maximilians Universität München, Munich, Germany
| | - John D. Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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11
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Locatelli M, Rottoli D, Mahmoud R, Abbate M, Corna D, Cerullo D, Tomasoni S, Remuzzi G, Zoja C, Benigni A, Macconi D. Endothelial Glycocalyx of Peritubular Capillaries in Experimental Diabetic Nephropathy: A Target of ACE Inhibitor-Induced Kidney Microvascular Protection. Int J Mol Sci 2023; 24:16543. [PMID: 38003732 PMCID: PMC10671403 DOI: 10.3390/ijms242216543] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Peritubular capillary rarefaction is a recurrent aspect of progressive nephropathies. We previously found that peritubular capillary density was reduced in BTBR ob/ob mice with type 2 diabetic nephropathy. In this model, we searched for abnormalities in the ultrastructure of peritubular capillaries, with a specific focus on the endothelial glycocalyx, and evaluated the impact of treatment with an angiotensin-converting enzyme inhibitor (ACEi). Mice were intracardially perfused with lanthanum to visualise the glycocalyx. Transmission electron microscopy analysis revealed endothelial cell abnormalities and basement membrane thickening in the peritubular capillaries of BTBR ob/ob mice compared to wild-type mice. Remodelling and focal loss of glycocalyx was observed in lanthanum-stained diabetic kidneys, associated with a reduction in glycocalyx components, including sialic acids, as detected through specific lectins. ACEi treatment preserved the endothelial glycocalyx and attenuated the ultrastructural abnormalities of peritubular capillaries. In diabetic mice, peritubular capillary damage was associated with an enhanced tubular expression of heparanase, which degrades heparan sulfate residues of the glycocalyx. Heparanase was also detected in renal interstitial macrophages that expressed tumor necrosis factor-α. All these abnormalities were mitigated by ACEi. Our findings suggest that, in experimental diabetic nephropathy, preserving the endothelial glycocalyx is important in order to protect peritubular capillaries from damage and loss.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy; (M.L.); (D.R.); (R.M.); (M.A.); (D.C.); (D.C.); (S.T.); (G.R.); (C.Z.); (D.M.)
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12
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Gaupp C, Schmid B, Tripal P, Edwards A, Daniel C, Zimmermann S, Goppelt-Struebe M, Willam C, Rosen S, Schley G. Reconfiguration and loss of peritubular capillaries in chronic kidney disease. Sci Rep 2023; 13:19660. [PMID: 37952029 PMCID: PMC10640592 DOI: 10.1038/s41598-023-46146-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 10/27/2023] [Indexed: 11/14/2023] Open
Abstract
Functional and structural alterations of peritubular capillaries (PTCs) are a major determinant of chronic kidney disease (CKD). Using a software-based algorithm for semiautomatic segmentation and morphometric quantification, this study analyzes alterations of PTC shape associated with chronic tubulointerstitial injury in three mouse models and in human biopsies. In normal kidney tissue PTC shape was predominantly elongated, whereas the majority of PTCs associated with chronic tubulointerstitial injury had a rounder shape. This was reflected by significantly reduced PTC luminal area, perimeter and diameters as well as by significantly increased circularity and roundness. These morphological alterations were consistent in all mouse models and human kidney biopsies. The mean circularity of PTCs correlated significantly with categorized glomerular filtration rates and the degree of interstitial fibrosis and tubular atrophy (IFTA) and classified the presence of CKD or IFTA. 3D reconstruction of renal capillaries revealed not only a significant reduction, but more importantly a substantial simplification and reconfiguration of the renal microvasculature in mice with chronic tubulointerstitial injury. Computational modelling predicted that round PTCs can deliver oxygen more homogeneously to the surrounding tissue. Our findings indicate that alterations of PTC shape represent a common and uniform reaction to chronic tubulointerstitial injury independent of the underlying kidney disease.
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Affiliation(s)
- Charlotte Gaupp
- Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
| | - Benjamin Schmid
- Optical Imaging Center Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Philipp Tripal
- Optical Imaging Center Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Aurélie Edwards
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Christoph Daniel
- Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany
| | - Stefan Zimmermann
- Department of Computer Science, University of Applied Sciences Worms, Worms, Germany
| | - Margarete Goppelt-Struebe
- Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
| | - Carsten Willam
- Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
| | - Seymour Rosen
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Gunnar Schley
- Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.
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13
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Liu F, Chen H, Cao C, Liang Y, Zhou Y. The role of toll-like receptors (TLRs) and their therapeutic applications in glomerulonephritis. Int Urol Nephrol 2023; 55:2845-2856. [PMID: 37060433 DOI: 10.1007/s11255-023-03592-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 04/07/2023] [Indexed: 04/16/2023]
Abstract
One of the most important features of innate immunity is the presence of a special group of pattern recognition receptors (PRRs) called toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), resulting in a quick and effective immune response to them. Glomerulonephritis (GN) is one of the most important categories of renal disorders characterized by destructive responses of the immune system to the glomerulus. To date, the association of TLRs as important innate immune system members with GN has been one of the topics that attracted the attention of researchers in this field. However, the exact role of these receptors in the immunopathogenesis of GN has not yet been fully discussed. Therefore, this study aims to overview the role of TLRs in GN and the possibility of using them as a potential therapeutic target.
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Affiliation(s)
- Feiyan Liu
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Huimin Chen
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Caixia Cao
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Yanlin Liang
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Ying Zhou
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China.
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14
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Manzéger A, Garmaa G, Mózes MM, Hansmann G, Kökény G. Pioglitazone Protects Tubular Epithelial Cells during Kidney Fibrosis by Attenuating miRNA Dysregulation and Autophagy Dysfunction Induced by TGF-β. Int J Mol Sci 2023; 24:15520. [PMID: 37958504 PMCID: PMC10649561 DOI: 10.3390/ijms242115520] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 10/20/2023] [Accepted: 10/21/2023] [Indexed: 11/15/2023] Open
Abstract
Excessive renal TGF-β production and pro-fibrotic miRNAs are important drivers of kidney fibrosis that lack any efficient treatment. Dysfunctional autophagy might play an important role in the pathogenesis. We aimed to study the yet unknown effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (Pio) on renal autophagy and miRNA dysregulation during fibrosis. Mouse primary tubular epithelial cells (PTEC) were isolated, pre-treated with 5 µM pioglitazone, and then stimulated with 10 ng/mL TGF-β1 for 24 h. Male 10-week-old C57Bl6 control (CTL) and TGF-β overexpressing mice were fed with regular chow (TGF) or Pio-containing chow (20 mg/kg/day) for 5 weeks (TGF + Pio). PTEC and kidneys were evaluated for mRNA and protein expression. In PTEC, pioglitazone attenuated (p < 0.05) the TGF-β-induced up-regulation of Col1a1 (1.4-fold), Tgfb1 (2.2-fold), Ctgf (1.5-fold), Egr2 (2.5-fold) mRNAs, miR-130a (1.6-fold), and miR-199a (1.5-fold), inhibited epithelial-to-mesenchymal transition, and rescued autophagy function. In TGF mice, pioglitazone greatly improved kidney fibrosis and related dysfunctional autophagy (increased LC3-II/I ratio and reduced SQSTM1 protein content (p < 0.05)). These were accompanied by 5-fold, 3-fold, 12-fold, and 2-fold suppression (p < 0.05) of renal Ccl2, Il6, C3, and Lgals3 mRNA expression, respectively. Our results implicate that pioglitazone counteracts multiple pro-fibrotic processes in the kidney, including autophagy dysfunction and miRNA dysregulation.
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Affiliation(s)
- Anna Manzéger
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
| | - Gantsetseg Garmaa
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
| | - Miklós M. Mózes
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
| | - Georg Hansmann
- Department of Pediatric Cardiology and Critical Care, Hannover Medical School, 30625 Hannover, Germany;
| | - Gábor Kökény
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
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15
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Zhu X, Zhao Y, Liu Y, Shi W, Yang J, Liu Z, Zhang X. Macrophages release IL11-containing filopodial tip vesicles and contribute to renal interstitial inflammation. Cell Commun Signal 2023; 21:293. [PMID: 37853428 PMCID: PMC10585809 DOI: 10.1186/s12964-023-01327-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/19/2023] [Indexed: 10/20/2023] Open
Abstract
Macrophage filopodia, which are dynamic nanotube-like protrusions, have mainly been studied in the context of pathogen clearance. The mechanisms by which they facilitate intercellular communication and mediate tissue inflammation remain poorly understood. Here, we show that macrophage filopodia produce a unique membrane structure called "filopodial tip vesicle" (FTV) that originate from the tip of macrophages filopodia. Filopodia tip-derived particles contain numerous internal-vesicles and function as cargo storage depots via nanotubular transport. Functional studies indicate that the shedding of FTV from filopodia tip allows the delivery of many molecular signalling molecules to fibroblasts. We observed that FTV derived from M1 macrophages and high glucose (HG)-stimulated macrophages (HG/M1-ftv) exhibit an enrichment of the chemokine IL11, which is critical for fibroblast transdifferentiation. HG/M1-ftv induce renal interstitial fibrosis in diabetic mice, while FTV inhibition or targeting FTV IL11- alleviates renal interstitial fibrosis, suggesting that the HG/M1-ftvIL11 pathway may be a novel mechanism underlying renal fibrosis in diabetic nephropathy. Collectively, FTV release could represent a novel function by which filopodia contribute to cell biological processes, and FTV is potentially associated with macrophage filopodia-related fibrotic diseases. Video Abstract.
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Affiliation(s)
- Xiaodong Zhu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yu Zhao
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yuqiu Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Wen Shi
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Junlan Yang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Zhihong Liu
- Jinling Hospital, National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Nanjing, Jiangsu, China
| | - Xiaoliang Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
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16
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Tiwari R, Sharma R, Rajendran G, Borkowski GS, An SY, Schonfeld M, O’Sullivan J, Schipma MJ, Zhou Y, Courbon G, David V, Quaggin SE, Thorp E, Chandel NS, Kapitsinou PP. Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.03.560700. [PMID: 37873349 PMCID: PMC10592920 DOI: 10.1101/2023.10.03.560700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1-3 in regulating post-ischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the three PHD isoforms in both mice and humans. We found that post-ischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. Single-cell RNA-seq analysis of the post-ischemic endothelial PHD1, PHD2 and PHD3 deficient (PHDTiEC) kidney revealed an endothelial glycolytic transcriptional signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed pro-inflammatory EC activation reducing monocyte-endothelial cell interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.
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Affiliation(s)
- Ratnakar Tiwari
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Rajni Sharma
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ganeshkumar Rajendran
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Gabriella S. Borkowski
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Si Young An
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Michael Schonfeld
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - James O’Sullivan
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Matthew J. Schipma
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Yalu Zhou
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Guillaume Courbon
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Valentin David
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Susan E. Quaggin
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Edward Thorp
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Navdeep S. Chandel
- Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Pinelopi P. Kapitsinou
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
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17
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Huang F, Ren X, Yuan B, Yang W, Xu L, Zhang J, Zhang H, Geng M, Li X, Zhang F, Xu J, Zhu W, Ren S, Meng L, Lu S. Systemic Mutation of Ncf1 Ameliorates Obstruction-Induced Renal Fibrosis While Macrophage-Rescued NCF1 Further Alleviates Renal Fibrosis. Antioxid Redox Signal 2023. [PMID: 37392014 DOI: 10.1089/ars.2022.0195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/02/2023]
Abstract
Aims: NCF1, a subunit of the NADPH oxidase 2 (NOX2), first described the expression in neutrophils and macrophages and participated in the pathogenesis from various systems. However, there are controversial findings on the role of NCF1 in different kinds of kidney diseases. In this study, we aim to pinpoint the specific role of NCF1 in the progression of renal fibrosis induced by obstruction. Results: In this study, NCF1 expression was upregulated in kidney biopsies of chronic kidney disease patients. The expression level of all subunits of the NOX2 complex was also significantly increased in the unilateral ureteral obstruction (UUO) kidney. Then, we used wild-type mice and Ncf1 mutant mice (Ncf1m1j mice) to perform UUO-induced renal fibrosis. Results demonstrated that Ncf1m1j mice exhibited mild renal fibrosis but increased macrophages count and CD11b+Ly6Chi macrophage proportion. Next, we compared the renal fibrosis degree between Ncf1m1j mice and Ncf1 macrophage-rescued mice (Ncf1m1j.Ncf1Tg-CD68 mice). We found that rescuing NCF1 expression in macrophages further alleviated renal fibrosis and decreased macrophage infiltration in the UUO kidney. In addition, flow cytometry data showed fewer CD11b+Ly6Chi macrophages in the kidney of the Ncf1m1j.Ncf1Tg-CD68 group than the Ncf1m1j group. Innovation: We first used the Ncf1m1j mice and Ncf1m1j.Ncf1Tg-CD68 mice to detect the role of NCF1 in the pathological process of renal fibrosis induced by obstruction. Also, we found that NCF1 expressed in different cell types exerts opposing effects on obstructive nephropathy. Conclusion: Taken together, our findings support that systemic mutation of Ncf1 ameliorates renal fibrosis induced by obstruction, and rescuing NCF1 in macrophages further alleviates renal fibrosis.
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Affiliation(s)
- Fumeng Huang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Xiaomin Ren
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Bingyu Yuan
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Wenbo Yang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Lexuan Xu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jing Zhang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Haonan Zhang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Manman Geng
- National Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaowei Li
- National Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fujun Zhang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jing Xu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Wenhua Zhu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Shuting Ren
- Department of Pathology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Liesu Meng
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
- National Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shemin Lu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
- National Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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18
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Lin L, Hu K. Macrophage Function Modulated by tPA Signaling in Mouse Experimental Kidney Disease Models. Int J Mol Sci 2023; 24:11067. [PMID: 37446244 DOI: 10.3390/ijms241311067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of blood coagulation, fibrinolysis, and matrix degradation, and has been shown to act as a cytokine to trigger various receptor-mediated intracellular signal pathways, modulating macrophage function in response to kidney injury. In this review, we discuss the current understanding of tPA-modulated macrophage function and underlying signaling mechanisms during kidney fibrosis and inflammation.
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Affiliation(s)
- Ling Lin
- Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - Kebin Hu
- Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, PA 17033, USA
- Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA
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19
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Oh H, Kwon O, Kong MJ, Park KM, Baek JH. Macrophages promote Fibrinogenesis during kidney injury. Front Med (Lausanne) 2023; 10:1206362. [PMID: 37425313 PMCID: PMC10325639 DOI: 10.3389/fmed.2023.1206362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 05/31/2023] [Indexed: 07/11/2023] Open
Abstract
Macrophages (Mø) are widely considered fundamental in the development of kidney fibrosis since Mø accumulation commonly aggravates kidney fibrosis, while Mø depletion mitigates it. Although many studies have aimed to elucidate Mø-dependent mechanisms linked to kidney fibrosis and have suggested various mechanisms, the proposed roles have been mostly passive, indirect, and non-unique to Mø. Therefore, the molecular mechanism of how Mø directly promote kidney fibrosis is not fully understood. Recent evidence suggests that Mø produce coagulation factors under diverse pathologic conditions. Notably, coagulation factors mediate fibrinogenesis and contribute to fibrosis. Thus, we hypothesized that kidney Mø express coagulation factors that contribute to the provisional matrix formation during acute kidney injury (AKI). To test our hypothesis, we probed for Mø-derived coagulation factors after kidney injury and uncovered that both infiltrating and kidney-resident Mø produce non-redundant coagulation factors in AKI and chronic kidney disease (CKD). We also identified F13a1, which catalyzes the final step of the coagulation cascade, as the most strongly upregulated coagulation factor in murine and human kidney Mø during AKI and CKD. Our in vitro experiments revealed that the upregulation of coagulation factors in Mø occurs in a Ca2 + -dependent manner. Taken together, our study demonstrates that kidney Mø populations express key coagulation factors following local injury, suggesting a novel effector mechanism of Mø contributing to kidney fibrosis.
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Affiliation(s)
- Hanna Oh
- Laboratory of Inflammation Research, Handong Global University, Pohang, Gyeongbuk, South Korea
- School of Life Science, Handong Global University, Pohang, Gyeongbuk, South Korea
| | - Ohbin Kwon
- Laboratory of Inflammation Research, Handong Global University, Pohang, Gyeongbuk, South Korea
- School of Life Science, Handong Global University, Pohang, Gyeongbuk, South Korea
| | - Min Jung Kong
- Department of Anatomy, BK21Plus, Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Kwon Moo Park
- Department of Anatomy, BK21Plus, Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Jea-Hyun Baek
- Laboratory of Inflammation Research, Handong Global University, Pohang, Gyeongbuk, South Korea
- School of Life Science, Handong Global University, Pohang, Gyeongbuk, South Korea
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20
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Trucas M, Burattini S, Porcu S, Simbula M, Ristaldi MS, Kowalik MA, Serra MP, Gobbi P, Battistelli M, Perra A, Quartu M. Multi-Organ Morphological Findings in a Humanized Murine Model of Sickle Cell Trait. Int J Mol Sci 2023; 24:10452. [PMID: 37445630 DOI: 10.3390/ijms241310452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/15/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ischemic multi-organ damage and consequently reduce life expectancy. On the other hand, sickle cell trait (SCT), the heterozygous beta-globin gene mutation, is still considered a benign condition. Although the mechanisms are not well understood, clinical evidence has recently shown that specific pathological symptoms can also be recognized in SCT carriers. So far, there are still scant data regarding the morphological modifications referable to possible multi-organ damage in the SCT condition. Therefore, after genotypic and hematological characterization, by conventional light microscopy and transmission electron microscopy (TEM), we investigated the presence of tissue alterations in 13 heterozygous Townes mice, one of the best-known animal models that, up to now, was used only for the study of the homozygous condition. We found that endothelial alterations, as among which the thickening of vessel basal lamina, are ubiquitous in the lung, liver, kidney, and spleen of SCT carrier mice. The lung shows the most significant alterations, with a distortion of the general tissue architecture, while the heart is the least affected. Collectively, our findings contribute novel data to the histopathological modifications at microscopic and ultrastructural levels, underlying the heterozygous beta-globin gene mutation, and indicate the translational suitability of the Townes model to characterize the features of multiple organ involvement in the SCT carriers.
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Affiliation(s)
- Marcello Trucas
- Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy
| | - Sabrina Burattini
- Department of Biomolecular Sciences, Campus Scientifico "Enrico Mattei", University of Urbino Carlo Bo, Via Ca' le Suore 2-Località Crocicchia, 61029 Urbino, Italy
| | - Susanna Porcu
- Italian National Research Council (CNR)-IRGB, Cittadella Universitaria Monserrato, 09042 Monserrato, Italy
| | - Michela Simbula
- Italian National Research Council (CNR)-IRGB, Cittadella Universitaria Monserrato, 09042 Monserrato, Italy
| | - Maria Serafina Ristaldi
- Italian National Research Council (CNR)-IRGB, Cittadella Universitaria Monserrato, 09042 Monserrato, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy
| | - Maria Pina Serra
- Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy
| | - Pietro Gobbi
- Department of Biomolecular Sciences, Campus Scientifico "Enrico Mattei", University of Urbino Carlo Bo, Via Ca' le Suore 2-Località Crocicchia, 61029 Urbino, Italy
| | - Michela Battistelli
- Department of Biomolecular Sciences, Campus Scientifico "Enrico Mattei", University of Urbino Carlo Bo, Via Ca' le Suore 2-Località Crocicchia, 61029 Urbino, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy
| | - Marina Quartu
- Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy
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21
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O'Sullivan ED, Mylonas KJ, Xin C, Baird DP, Carvalho C, Docherty MH, Campbell R, Matchett KP, Waddell SH, Walker AD, Gallagher KM, Jia S, Leung S, Laird A, Wilflingseder J, Willi M, Reck M, Finnie S, Pisco A, Gordon-Keylock S, Medvinsky A, Boulter L, Henderson NC, Kirschner K, Chandra T, Conway BR, Hughes J, Denby L, Bonventre JV, Ferenbach DA. Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis. Sci Transl Med 2023; 15:eabn0736. [PMID: 37256934 PMCID: PMC11977576 DOI: 10.1126/scitranslmed.abn0736] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 05/10/2023] [Indexed: 06/02/2023]
Abstract
Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.
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Affiliation(s)
- Eoin D O'Sullivan
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
- Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
| | - Katie J Mylonas
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Cuiyan Xin
- Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - David P Baird
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Cyril Carvalho
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Marie-Helena Docherty
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Ross Campbell
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Kylie P Matchett
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Scott H Waddell
- Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Alexander D Walker
- Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Kevin M Gallagher
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
- Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Siyang Jia
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Steve Leung
- Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Alexander Laird
- Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Julia Wilflingseder
- Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Department of Physiology and Pathophysiology, University of Veterinary Medicine, Veterinärplatz 1, 1210 Vienna, Austria
| | - Michaela Willi
- Laboratory of Genetics and Physiology, NIDDK, NIH, Bethesda, MD 20892, USA
| | - Maximilian Reck
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Sarah Finnie
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Angela Pisco
- Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
| | | | - Alexander Medvinsky
- Centre for Regenerative Medicine. University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Luke Boulter
- Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Neil C Henderson
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
- Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Kristina Kirschner
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK
| | - Tamir Chandra
- Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Bryan R Conway
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Jeremy Hughes
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Laura Denby
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Joseph V Bonventre
- Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - David A Ferenbach
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
- Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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22
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Lee B, Kang W, Oh SH, Cho S, Shin I, Oh EJ, Kim YJ, Ahn JS, Yook JM, Jung SJ, Lim JH, Kim YL, Cho JH, Oh WY. In vivo imaging of renal microvasculature in a murine ischemia-reperfusion injury model using optical coherence tomography angiography. Sci Rep 2023; 13:6396. [PMID: 37076541 PMCID: PMC10115874 DOI: 10.1038/s41598-023-33295-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/11/2023] [Indexed: 04/21/2023] Open
Abstract
Optical coherence tomography angiography (OCTA) provides three-dimensional structural and semiquantitative imaging of microvasculature in vivo. We developed an OCTA imaging protocol for a murine kidney ischemia-reperfusion injury (IRI) model to investigate the correlation between renal microvascular changes and ischemic damage. Mice were divided into mild and moderate IRI groups according to the duration of ischemia (10 and 35 mins, respectively). Each animal was imaged at baseline; during ischemia; and at 1, 15, 30, 45, and 60 mins after ischemia. Amplitude decorrelation OCTA images were constructed with 1.5-, 3.0-, and 5.8-ms interscan times, to calculate the semiquantitative flow index in the superficial (50-70 μm) and the deep (220-340 μm) capillaries of the renal cortex. The mild IRI group showed no significant flow index change in both the superfial and the deep layers. The moderate IRI group showed a significantly decreased flow index from 15 and 45 mins in the superficial and deep layers, respectively. Seven weeks after IRI induction, the moderate IRI group showed lower kidney function and higher collagen deposition than the mild IRI group. OCTA imaging of the murine IRI model revealed changes in superficial blood flow after ischemic injury. A more pronounced decrease in superficial blood flow than in deep blood flow was associated with sustained dysfunction after IRI. Further investigation on post-IRI renal microvascular response using OCTA may improve our understanding of the relationship between the degree of ischemic insult and kidney function.
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Affiliation(s)
- ByungKun Lee
- Department of Mechanical Engineering, KAIST, Daejeon, Republic of Korea
- KI for Health Science and Technology, KAIST, Daejeon, Republic of Korea
| | - Woojae Kang
- Department of Mechanical Engineering, KAIST, Daejeon, Republic of Korea
- KI for Health Science and Technology, KAIST, Daejeon, Republic of Korea
| | - Se-Hyun Oh
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Seungwan Cho
- Department of Mechanical Engineering, KAIST, Daejeon, Republic of Korea
- KI for Health Science and Technology, KAIST, Daejeon, Republic of Korea
| | - Inho Shin
- Department of Mechanical Engineering, KAIST, Daejeon, Republic of Korea
- KI for Health Science and Technology, KAIST, Daejeon, Republic of Korea
| | - Eun-Joo Oh
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - You-Jin Kim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Ji-Sun Ahn
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Ju-Min Yook
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Soo-Jung Jung
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Jeong-Hoon Lim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Yong-Lim Kim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Jang-Hee Cho
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea.
- Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea.
| | - Wang-Yuhl Oh
- Department of Mechanical Engineering, KAIST, Daejeon, Republic of Korea.
- KI for Health Science and Technology, KAIST, Daejeon, Republic of Korea.
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23
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Gonçalves LED, Andrade-Silva M, Basso PJ, Câmara NOS. Vitamin D and chronic kidney disease: Insights on lipid metabolism of tubular epithelial cell and macrophages in tubulointerstitial fibrosis. Front Physiol 2023; 14:1145233. [PMID: 37064892 PMCID: PMC10090472 DOI: 10.3389/fphys.2023.1145233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/15/2023] [Indexed: 03/31/2023] Open
Abstract
Chronic kidney disease (CKD) has been recognized as a significant global health problem due to being an important contributor to morbidity and mortality. Inflammation is the critical event that leads to CKD development orchestrated by a complex interaction between renal parenchyma and immune cells. Particularly, the crosstalk between tubular epithelial cells (TECs) and macrophages is an example of the critical cell communication in the kidney that drives kidney fibrosis, a pathological feature in CKD. Metabolism dysregulation of TECs and macrophages can be a bridge that connects inflammation and fibrogenesis. Currently, some evidence has reported how cellular lipid disturbances can affect kidney disease and cause tubulointerstitial fibrosis highlighting the importance of investigating potential molecules that can restore metabolic parameters. Vitamin D (VitD) is a hormone naturally produced by mammalian cells in a coordinated manner by the skin, liver, and kidneys. VitD deficiency or insufficiency is prevalent in patients with CKD, and serum levels of VitD are inversely correlated with the degree of kidney inflammation and renal function. Proximal TECs and macrophages produce the active form of VitD, and both express the VitD receptor (VDR) that evidence the importance of this nutrient in regulating their functions. However, whether VitD signaling drives physiological and metabolism improvement of TECs and macrophages during kidney injury is an open issue to be debated. In this review, we brought to light VitD as an important metabolic modulator of lipid metabolism in TECs and macrophages. New scientific approaches targeting VitD e VDR signaling at the cellular metabolic level can provide a better comprehension of its role in renal physiology and CKD progression.
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Affiliation(s)
- Luís Eduardo D. Gonçalves
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Magaiver Andrade-Silva
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Laboratory of Experimental e Clinical Immunology, Department of Clinical Medicine, Faculty of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Paulo José Basso
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- *Correspondence: Paulo José Basso, ; Niels O. S. Câmara,
| | - Niels O. S. Câmara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Laboratory of Experimental e Clinical Immunology, Department of Clinical Medicine, Faculty of Medicine, Federal University of São Paulo, São Paulo, Brazil
- *Correspondence: Paulo José Basso, ; Niels O. S. Câmara,
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24
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Saifi MA, Bansod S, Godugu C. COVID-19 and fibrosis: Mechanisms, clinical relevance, and future perspectives. Drug Discov Today 2022; 27:103345. [PMID: 36075378 PMCID: PMC9444298 DOI: 10.1016/j.drudis.2022.103345] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 07/19/2022] [Accepted: 09/01/2022] [Indexed: 01/08/2023]
Abstract
Coronavirus 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has had significant impacts worldwide since its emergence in December, 2019. Despite a high recovery rate, there is a growing concern over its residual, long-term effects. However, because of a lack of long-term data, we are still far from establishing a consensus on post-COVID-19 complications. The deposition of excessive extracellular matrix (ECM), known as fibrosis, has been observed in numerous survivors of COVID-19. Given the exceptionally high number of individuals affected, there is an urgent need to address the emergence of fibrosis post-COVID-19. In this review, we discuss the clinical relevance of COVID-19-associated fibrosis, the current status of antifibrotic agents, novel antifibrotic targets, and challenges to its management.
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Affiliation(s)
- Mohd Aslam Saifi
- Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500 037, India
| | - Sapana Bansod
- Department of Internal Medicine, Oncology Division, Washington University, School of Medicine, St Louis, MO 63110, USA
| | - Chandraiah Godugu
- Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500 037, India.
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25
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Osaki Y, Manolopoulou M, Ivanova AV, Vartanian N, Mignemi MP, Kern J, Chen J, Yang H, Fogo AB, Zhang M, Robinson-Cohen C, Gewin LS. Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease. JCI Insight 2022; 7:e158754. [PMID: 35730565 PMCID: PMC9309053 DOI: 10.1172/jci.insight.158754] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/04/2022] [Indexed: 11/17/2022] Open
Abstract
Acute and chronic kidney injuries induce increased cell cycle progression in renal tubules. While increased cell cycle progression promotes repair after acute injury, the role of ongoing tubular cell cycle progression in chronic kidney disease is unknown. Two weeks after initiation of chronic kidney disease, we blocked cell cycle progression at G1/S phase by using an FDA-approved, selective inhibitor of CDK4/6. Blocking CDK4/6 improved renal function and reduced tubular injury and fibrosis in 2 murine models of chronic kidney disease. However, selective deletion of cyclin D1, which complexes with CDK4/6 to promote cell cycle progression, paradoxically increased tubular injury. Expression quantitative trait loci (eQTLs) for CCND1 (cyclin D1) and the CDK4/6 inhibitor CDKN2B were associated with eGFR in genome-wide association studies. Consistent with the preclinical studies, reduced expression of CDKN2B correlated with lower eGFR values, and higher levels of CCND1 correlated with higher eGFR values. CDK4/6 inhibition promoted tubular cell survival, in part, through a STAT3/IL-1β pathway and was dependent upon on its effects on the cell cycle. Our data challenge the paradigm that tubular cell cycle progression is beneficial in the context of chronic kidney injury. Unlike the reparative role of cell cycle progression following acute kidney injury, these data suggest that blocking cell cycle progression by inhibiting CDK4/6, but not cyclin D1, protects against chronic kidney injury.
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Affiliation(s)
- Yosuke Osaki
- Division of Nephrology and Hypertension, Department of Medicine, Washington University St. Louis, St. Louis, Missouri, USA
- Division of Nephrology and Hypertension, Department of Medicine, and
| | | | - Alla V. Ivanova
- Division of Nephrology and Hypertension, Department of Medicine, and
| | | | | | - Justin Kern
- Division of Nephrology and Hypertension, Department of Medicine, Washington University St. Louis, St. Louis, Missouri, USA
| | - Jianchun Chen
- Division of Nephrology and Hypertension, Department of Medicine, and
| | - Haichun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, USA
| | - Agnes B. Fogo
- Division of Nephrology and Hypertension, Department of Medicine, and
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, USA
| | - Mingzhi Zhang
- Division of Nephrology and Hypertension, Department of Medicine, and
| | | | - Leslie S. Gewin
- Division of Nephrology and Hypertension, Department of Medicine, Washington University St. Louis, St. Louis, Missouri, USA
- Division of Nephrology and Hypertension, Department of Medicine, and
- Department of Medicine, Veterans Affairs Hospital, St. Louis VA, St. Louis, Missouri, USA
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26
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Sedmaki K, Karnam K, Sharma P, Mahale A, Routholla G, Ghosh B, Prakash Kulkarni O. HDAC6 inhibition attenuates renal injury by reducing IL-1β secretion and RIP kinase mediated necroptosis in acute oxalate nephropathy. Int Immunopharmacol 2022; 110:108919. [PMID: 35717839 DOI: 10.1016/j.intimp.2022.108919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/19/2022] [Accepted: 05/31/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Pathogenesis of acute kidney injury is driven by necro-inflammation, which is comprised of IL-1β mediated inflammation and RIP-1 mediated tubular necroptosis. HDAC6 is reported to regulate both inflammation and cell death. In the present study, we explored the role of HDAC6 in the lysosomal exocytosis of IL-1β and RIP-1 mediated necroptosis in the context of oxalate nephropathy. METHODS Raw 264.7 macrophages and NRK52E stimulated with oxalate crystals and LPS with or without HDAC6 inhibitor for in vitro experiments. Acute oxalate nephropathy was induced in C57BL/6 mice by injecting sodium oxalate (75 mg/kg). For the drug intervention study, Tubastain A (TSA) was given an hour before injection of sodium oxalate. Mice were sacrificed 24 hrs after the oxalate injection, blood and kidney were harvested. Blood samples were analyzed for BUN and IL-1β levels. Renal tissues were analyzed for histology, immunohistochemistry, RNA, and protein expression. RESULTS HDAC6 and IL-1β upregulated in crystal stimulated macrophages and acute oxalate nephropathy. Pre-treatment of macrophages with TSA reduced IL-1β in supernatant without affecting the expression of pro-IL-1β and mature IL-1β in cell lysate. The effect of TSA on IL-1β secretion was influenced by tubulin acetylation. Renal epithelial cell NRK52E stimulated with crystals showed upregulation of necroptosis pathway markers and concentration-dependent cell death. TSA inhibited RIP-1, RIP3, and MLKL expression along with p-MLKL in stimulated epithelial cells. TSA treatment of oxalate nephropathy mice showed decreased inflammation and tubular cell death by regulating IL-1β and necroptosis and reduced renal injury. CONCLUSION This study highlights the role of HDAC6 in regulating the tubulin-mediated secretion of IL-1β and RIP kinase mediated necroptosis in acute oxalate nephropathy.
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Affiliation(s)
- Kavitha Sedmaki
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Kalyani Karnam
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Pravesh Sharma
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Ashutosh Mahale
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Ganesh Routholla
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Balaram Ghosh
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Onkar Prakash Kulkarni
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India.
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27
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Core fucosylation involvement in the paracrine regulation of proteinuria-induced renal interstitial fibrosis evaluated with the use of a microfluidic chip. Acta Biomater 2022; 142:99-112. [PMID: 35189379 DOI: 10.1016/j.actbio.2022.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 11/23/2022]
Abstract
Proteinuria is a clinical manifestation of chronic kidney disease that aggravates renal interstitial fibrosis (RIF), in which injury of peritubular microvessels is an important event. However, the changes in peritubular microvessels induced by proteinuria and their molecular mechanisms remain unclear. Thus, we aimed to develop a co-culture microfluidic device that contains renal tubules and peritubular microvessels to create a proteinuria model. We found that protein overload in the renal tubule induced trans-differentiation and apoptosis of endothelial cells (ECs) and pericytes. Moreover, profiling of secreted proteins in this model revealed that a paracrine network between tubules and microvessels was activated in proteinuria-induced microvascular injury. Multiple cytokine receptors in this paracrine network were core-fucosylated. Inhibition of core fucosylation significantly reduced ligand-receptor binding ability and blocked downstream pathways, alleviating trans-differentiation and apoptosis of ECs and pericytes. Furthermore, the protective effect of genetic FUT8 deficiency on proteinuria overload-induced RIF and pericyte-myofibroblast trans-differentiation was validated in FUT8 knockout heterozygous mice. In conclusion, we constructed and used a multiple-unit integrated microfluidic device to uncover the mechanism of proteinuria-induced RIF. Furthermore, FUT8 may serve as a hub-like therapeutic target to alleviate peritubular microvascular injury in RIF. STATEMENT OF SIGNIFICANCE: In this study, we constructed a multiple-unit integrated renal tubule-vascular chip. We reproduced human proteinuria on the chip and found that multiple receptors were modified by FUT8-catalyzed core fucosylation (CF) involved in the cross-talk between renal tubules and peritubular microvessels in proteinuria-induced RIF, and inhibiting the FUT8 of receptors could block the tubule-microvessel paracrine network and reverse the damage of peritubular microvessels and renal interstitial fibrosis. This tubule-vascular chip may provide a prospective platform to facilitate future investigations into the mechanisms of kidney diseases, and target-FUT8 inhibition may be an innovative and potential therapeutic strategy for RIF induced by proteinuria.
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Treatment of Chronic Kidney Disease with Extracellular Vesicles from Mesenchymal Stem Cells and CD133 + Expanded Cells: A Comparative Preclinical Analysis. Int J Mol Sci 2022; 23:ijms23052521. [PMID: 35269664 PMCID: PMC8910174 DOI: 10.3390/ijms23052521] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 01/06/2023] Open
Abstract
Chronic kidney disease (CKD) is characterized by structural abnormalities and the progressive loss of kidney function. Extracellular vesicles (EVs) from human umbilical cord tissue (hUCT)-derived mesenchymal stem cells (MSCs) and expanded human umbilical cord blood (hUCB)-derived CD133+ cells (eCD133+) maintain the characteristics of the parent cells, providing a new form of cell-free treatment. We evaluated the effects of EVs from hUCT-derived MSCs and hUCB-derived CD133+ cells on rats with CDK induced by an adenine-enriched diet. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis (NTA) and electron microscopy. The animals were randomized and divided into the MSC-EV group, eEPC-EV group and control group. Infusions occurred on the seventh and 14th days after CKD induction. Evaluations of kidney function were carried out by biochemical and histological analyses. Intense labeling of the α-SMA protein was observed when comparing the control with MSC-EVs. In both groups treated with EVs, a significant increase in serum albumin was observed, and the increase in cystatin C was inhibited. The results indicated improvements in renal function in CKD, demonstrating the therapeutic potential of EVs derived from MSCs and eCD133+ cells and suggesting the possibility that in the future, more than one type of EV will be used concurrently.
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Olfactory receptors contribute to progression of kidney fibrosis. NPJ Syst Biol Appl 2022; 8:8. [PMID: 35181660 PMCID: PMC8857310 DOI: 10.1038/s41540-022-00217-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 01/21/2022] [Indexed: 11/08/2022] Open
Abstract
Olfactory receptors (ORs) which are mainly known as odor-sensors in the olfactory epithelium are shown to be expressed in several non-sensory tissues. Despite the specified role of some of these receptors in normal physiology of the kidney, little is known about their potential effect in renal disorders. In this study, using the holistic view of systems biology, it was determined that ORs are significantly changed during the progression of kidney fibrosis. For further validation, common differentially expressed ORs resulted from reanalysis of two time-course microarray datasets were selected for experimental evaluation in a validated murine model of unilateral ureteral obstruction (UUO). Transcriptional analysis by real-time quantitative polymerase chain reaction demonstrated considerable changes in the expression pattern of Olfr433, Olfr129, Olfr1393, Olfr161, and Olfr622 during the progression of kidney fibrosis. For localization of these ORs, single-cell RNA-sequencing datasets of normal and UUO mice were reanalyzed. Results showed that Olfr433 is highly expressed in macrophages in day-2 and 7 post-injury in UUO mice and not in normal subgroups. Besides, like previous findings, Olfr1393 was shown to be expressed prominently in the proximal tubular cells of the kidney. In conclusion, our combinatorial temporal approach to the underlying mechanisms of chronic kidney disease highlighted the potential role of ORs in progression of fibrosis. The expression of Olfr433 in the macrophages provides some clue about its relation to molecular mechanisms promoted in the fibrotic kidney. The proposed ORs in this study could be the subject of further functional assessments in the future.
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He D, Li Q, Du G, Meng G, Sun J, Chen S. An Integration of Network Pharmacology and Experimental Verification to Investigate the Mechanism of Guizhi to Treat Nephrotic Syndrome. Front Pharmacol 2021; 12:755421. [PMID: 34925015 PMCID: PMC8675883 DOI: 10.3389/fphar.2021.755421] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 11/11/2021] [Indexed: 01/20/2023] Open
Abstract
Background: Guizhi has the pharmacological activity of anti-inflammatory. However, the effect mechanism of Guizhi against nephrotic syndrome (NS) remains unclear. A network pharmacological approach with experimental verification in vitro and in vivo was performed to investigate the potential mechanisms of Guizhi to treat NS. Methods: Active compounds and potential targets of Guizhi, as well as the related targets of NS were obtained from the public databases. The intersecting targets of Guizhi and NS were obtained through Venny 2.1.0. The key targets and signaling pathways were determined by protein-protein interaction (PPI), genes ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis. And the overall network was constructed with Cytoscape. Molecular docking verification was carried out by AutoDock Vina. Finally, in vitro and in vivo experiments were performed to verify the mechanism of Guizhi to treat NS. Results: 63 intersecting targets were obtained, and the top five key targets mainly involed in NF- Kappa B and MAPK signaling pathway. In the overall network, cinnamaldehyde (CA) was the top one active compound with the highest degree value. The molecular docking showed that the top five key targets were of good binding activity with the active components of Guizhi. To in vitro experiment, CA, the main active component of Guizhi, inhibited the secretion of IL-1β, IL-6, TNF-α in LPS challenged RAW264.7 cells, and down regulated the protein expression of p-NF-κB p65 and p-p38 MAPK in LPS challenged RAW264.7 cells. In vitro experiment showed that, 24 urinary protein and renal function were increased in ADR group. To western blot, CA down regulated the protein expression of p-p38 MAPK in rats of adriamycin-induced nephropathy. Conclusion: CA might be the main active component of Guizhi to treat NS, and the underlying mechanism might mainly be achieved by inhibiting MAPK signaling pathway.
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Affiliation(s)
- Dan He
- School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qiang Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangli Du
- School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guofeng Meng
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jijia Sun
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shaoli Chen
- School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Shen M, Pan X, Gao Y, Ye H, Zhang J, Chen Y, Pan M, Huang W, Xu X, Zhao Y, Jin L. LncRNA CRNDE Exacerbates IgA Nephropathy Progression by Promoting NLRP3 Inflammasome Activation in Macrophages. Immunol Invest 2021; 51:1515-1527. [PMID: 34747317 DOI: 10.1080/08820139.2021.1989461] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Activation of NLRP3 inflammasome in macrophages contributes greatly to IgA nephropathy (IgAN) progression. This study intended to investigate the underlying mechanism of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the development of IgAN. METHODS We examined the expression levels of colorectal neoplasia differentially expressed (CRNDE), NLRP3 inflammasome-related proteins in peripheral blood mononuclear cells (PBMCs) and J774A.1 cells and detected inflammatory cytokine levels in the serum of IgAN patients and cell supernatants of in vitro IgAN model. RNA pull-down and RNA immunoprecipitation (RIP) experiments were conducted to evaluate the interaction between CRNDE and NLRP3. Then, the ubiquitin level of NLRP3 and its binding ability to TRIM family member 31 (TRIM31) were determined. RESULTS Compared with the control group, the expressions of CRNDE and NLRP3 inflammasome-related proteins in PBMCs and J774A.1 cells and levels of IL-1β, TNF-α and IL-12 in serum of IgAN patients and cell supernatants of IgA-IC-induced J774A.1 cells were all increased. CRNDE silencing down-regulated NLRP3 inflammasome-related proteins and the levels of IL-1β, TNF-α and IL-12 in cell supernatants, while NLRP3 overexpression reversed these effects. Additionally, CRNDE could interact with NLRP3 and promote NLRP3 expression. Furthermore, inhibition of CRNDE reduced NLRP3 protein level and promoted TRIM31-mediated NLRP3 ubiquitination and degradation. CONCLUSION CRNDE exacerbates IgA nephropathy progression through restraining ubiquitination and degradation of NLRP3 and facilitating NLRP3 inflammasome activation in macrophages.
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Affiliation(s)
- Meng Shen
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Xinyue Pan
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Yingjie Gao
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Hanyang Ye
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Jing Zhang
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Yan Chen
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Min Pan
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Wenwen Huang
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Xiaoyan Xu
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Yanling Zhao
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
| | - Lingwei Jin
- Department of Nephropathy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R China
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Baranwal G, Creed HA, Black LM, Auger A, Quach AM, Vegiraju R, Eckenrode HE, Agarwal A, Rutkowski JM. Expanded renal lymphatics improve recovery following kidney injury. Physiol Rep 2021; 9:e15094. [PMID: 34806312 PMCID: PMC8606868 DOI: 10.14814/phy2.15094] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) is a major cause of patient mortality and a major risk multiplier for the progression to chronic kidney disease (CKD). The mechanism of the AKI to CKD transition is complex but is likely mediated by the extent and length of the inflammatory response following the initial injury. Lymphatic vessels help to maintain tissue homeostasis through fluid, macromolecule, and immune modulation. Increased lymphatic growth, or lymphangiogenesis, often occurs during inflammation and plays a role in acute and chronic disease processes. What roles renal lymphatics and lymphangiogenesis play in AKI recovery and CKD progression remains largely unknown. To determine if the increased lymphatic density is protective in the response to kidney injury, we utilized a transgenic mouse model with inducible, kidney-specific overexpression of the lymphangiogenic protein vascular endothelial growth factor-D to expand renal lymphatics. "KidVD" mouse kidneys were injured using inducible podocyte apoptosis and proteinuria (POD-ATTAC) or bilateral ischemia reperfusion. In the acute injury phase of both models, KidVD mice demonstrated a similar loss of function measured by serum creatinine and glomerular filtration rate compared to their littermates. While the initial inflammatory response was similar, KidVD mice demonstrated a shift toward more CD4+ and fewer CD8+ T cells in the kidney. Reduced collagen deposition and improved functional recovery over time was also identified in KidVD mice. In KidVD-POD-ATTAC mice, an increased number of podocytes were counted at 28 days post-injury. These data demonstrate that increased lymphatic density prior to injury alters the injury recovery response and affords protection from CKD progression.
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Affiliation(s)
- Gaurav Baranwal
- Division of Lymphatic BiologyDepartment of Medical PhysiologyTexas A&M University College of MedicineBryanTexasUSA
| | - Heidi A. Creed
- Division of Lymphatic BiologyDepartment of Medical PhysiologyTexas A&M University College of MedicineBryanTexasUSA
| | - Laurence M. Black
- Department of MedicineUniversity of Alabama at BirminghamBirminghamAlabamaUSA
- Nephrology Research and Training CenterUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Alexa Auger
- Division of Lymphatic BiologyDepartment of Medical PhysiologyTexas A&M University College of MedicineBryanTexasUSA
| | - Alexander M. Quach
- Division of Lymphatic BiologyDepartment of Medical PhysiologyTexas A&M University College of MedicineBryanTexasUSA
| | - Rahul Vegiraju
- Division of Lymphatic BiologyDepartment of Medical PhysiologyTexas A&M University College of MedicineBryanTexasUSA
| | - Han E. Eckenrode
- Department of MedicineUniversity of Alabama at BirminghamBirminghamAlabamaUSA
- Nephrology Research and Training CenterUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Anupam Agarwal
- Department of MedicineUniversity of Alabama at BirminghamBirminghamAlabamaUSA
- Nephrology Research and Training CenterUniversity of Alabama at BirminghamBirminghamAlabamaUSA
- Department of Veterans AffairsBirmingham Veterans Administration Medical CenterBirminghamAlabamaUSA
| | - Joseph M. Rutkowski
- Division of Lymphatic BiologyDepartment of Medical PhysiologyTexas A&M University College of MedicineBryanTexasUSA
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Zeng H, Yang X, Luo S, Zhou Y. The Advances of Single-Cell RNA-Seq in Kidney Immunology. Front Physiol 2021; 12:752679. [PMID: 34721077 PMCID: PMC8548579 DOI: 10.3389/fphys.2021.752679] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 09/20/2021] [Indexed: 01/14/2023] Open
Abstract
Kidney diseases are highly prevalent and treatment is costly. Immune cells play important roles in kidney diseases; however, it has been challenging to investigate the contribution of each cell type in kidney pathophysiology. Recently, the development of single-cell sequencing technology has allowed the extensive study of immune cells in blood, secondary lymphoid tissues, kidney biopsy and urine samples, helping researchers generate a comprehensive immune cell atlas for various kidney diseases. Here, we discuss several recent studies using scRNA-seq technology to explore the immune-related kidney diseases, including lupus nephritis, diabetic kidney disease, IgA nephropathy, and anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. Application of scRNA-seq successfully defined the transcriptome profiles of resident and infiltrating immune cells, as well as the intracellular communication networks between immune and adjacent cells. In addition, the discovery of similar immune cells in blood and urine suggests the possibility of examining kidney immunity without biopsy. In conclusion, these immune cell atlases will increase our understanding of kidney immunology and contribute to novel therapeutics for patients with kidney diseases.
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Affiliation(s)
- Honghui Zeng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoqiang Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Siweier Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yiming Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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Xu H, Wu T, Huang L. Therapeutic and delivery strategies of phytoconstituents for renal fibrosis. Adv Drug Deliv Rev 2021; 177:113911. [PMID: 34358538 DOI: 10.1016/j.addr.2021.113911] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/07/2021] [Accepted: 07/29/2021] [Indexed: 12/11/2022]
Abstract
Chronic kidney disease (CKD) is one of the most common diseases endangering human health and life. By 2030, 14 per 100,000 people may die from CKD. Renal fibrosis (RF) is an important intermediate link and the final pathological change during CKD progression to the terminal stage. Therefore, identifying safe and effective treatment methods for RF has become an important goal. In 2018, the World Health Organization introduced traditional Chinese medicine into its effective global medical program. Various phytoconstituents that affect the RF process have been extracted from different plants. Here, we review the potential therapeutic capabilities of active phytoconstituents in RF treatment and discuss how phytoconstituents can be structurally modified or combined with other ingredients to enhance efficiency and reduce toxicity. We also summarize phytoconstituent delivery strategies to overcome renal barriers and improve bioavailability and targeting.
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Affiliation(s)
- Huan Xu
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China.
| | - Tianyi Wu
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| | - Leaf Huang
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
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35
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Abstract
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is considered that the pathogenesis of IgAN involves the ‘multiple hit theory’ and the immune-inflammatory mechanism; however, these theories have certain limitations. The gold standard for diagnosing IgAN is still renal biopsy. Although renal biopsy is accurate, it is traumatic and is associated with some risks and limitations, so there is a need for non-invasive diagnostic methods. According to recent studies, microRNAs (miRNAs) play important roles in the occurrence and development of IgAN; thus, they provide the possibility of the noninvasive diagnosis of IgAN and also have some value in predicting prognosis. This review summarizes the current research status of miRNAs in the occurrence, development, diagnosis, and prognosis of IgAN. We also highlight some interesting and challenging points that require further study.
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Affiliation(s)
- Xingchen Yao
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Renal Research Institution, Zhengzhou University, Zhengzhou, China
| | - Yaling Zhai
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Renal Research Institution, Zhengzhou University, Zhengzhou, China
| | - Huanping An
- Medicine Experiment Center, Hanzhong Vocational and Technical College, Hanzhong, China
| | - Jingge Gao
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Renal Research Institution, Zhengzhou University, Zhengzhou, China
| | - Yazhuo Chen
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Renal Research Institution, Zhengzhou University, Zhengzhou, China
| | - Wenhui Zhang
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Renal Research Institution, Zhengzhou University, Zhengzhou, China
| | - Zhanzheng Zhao
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Renal Research Institution, Zhengzhou University, Zhengzhou, China
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Wang X, Chen J, Xu J, Xie J, Harris DCH, Zheng G. The Role of Macrophages in Kidney Fibrosis. Front Physiol 2021; 12:705838. [PMID: 34421643 PMCID: PMC8378534 DOI: 10.3389/fphys.2021.705838] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 06/07/2021] [Indexed: 12/27/2022] Open
Abstract
The phenotypic heterogeneity and functional diversity of macrophages confer on them complexed roles in the development and progression of kidney diseases. After kidney injury, bone marrow-derived monocytes are rapidly recruited to the glomerulus and tubulointerstitium. They are activated and differentiated on site into pro-inflammatory M1 macrophages, which initiate Th1-type adaptive immune responses and damage normal tissues. In contrast, anti-inflammatory M2 macrophages induce Th2-type immune responses, secrete large amounts of TGF-β and anti-inflammatory cytokines, transform into αSMA+ myofibroblasts in injured kidney, inhibit immune responses, and promote wound healing and tissue fibrosis. Previous studies on the role of macrophages in kidney fibrosis were mainly focused on inflammation-associated injury and injury repair. Apart from macrophage-secreted profibrotic cytokines, such as TGF-β, evidence for a direct contribution of macrophages to kidney fibrosis is lacking. However, under inflammatory conditions, Wnt ligands are derived mainly from macrophages and Wnt signaling is central in the network of multiple profibrotic pathways. Largely underinvestigated are the direct contribution of macrophages to profibrotic signaling pathways, macrophage phenotypic heterogeneity and functional diversity in relation to kidney fibrosis, and on their cross-talk with other cells in profibrotic signaling networks that cause fibrosis. Here we aim to provide an overview on the roles of macrophage phenotypic and functional diversity in their contribution to pro-fibrotic signaling pathways, and on the therapeutic potential of targeting macrophages for the treatment of kidney fibrosis.
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Affiliation(s)
- Xiaoling Wang
- Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, China
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan, China
| | - Jianwei Chen
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Jun Xu
- Department of General Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jun Xie
- Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, China
| | - David C. H. Harris
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Guoping Zheng
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
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Macrophages and Stem Cells-Two to Tango for Tissue Repair? Biomolecules 2021; 11:biom11050697. [PMID: 34066618 PMCID: PMC8148606 DOI: 10.3390/biom11050697] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/25/2022] Open
Abstract
Macrophages (MCs) are present in all tissues, not only supporting homeostasis, but also playing an important role in organogenesis, post-injury regeneration, and diseases. They are a heterogeneous cell population due to their origin, tissue specificity, and polarization in response to aggression factors, depending on environmental cues. Thus, as pro-inflammatory M1 phagocytic MCs, they contribute to tissue damage and even fibrosis, but the anti-inflammatory M2 phenotype participates in repairing processes and wound healing through a molecular interplay with most cells in adult stem cell niches. In this review, we emphasize MC phenotypic heterogeneity in health and disease, highlighting their systemic and systematic contribution to tissue homeostasis and repair. Unraveling the intervention of both resident and migrated MCs on the behavior of stem cells and the regulation of the stem cell niche is crucial for opening new perspectives for novel therapeutic strategies in different diseases.
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Liu L, Ma F, Hao Y, Yi Z, Yu X, Xu B, Wei C, Hu J. Integrative Informatics Analysis of Transcriptome and Identification of Interacted Genes in the Glomeruli and Tubules in CKD. Front Med (Lausanne) 2021; 7:615306. [PMID: 33644086 PMCID: PMC7906987 DOI: 10.3389/fmed.2020.615306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/23/2020] [Indexed: 11/16/2022] Open
Abstract
Chronic kidney disease (CKD) is a complex disease in which the renal function is compromised chronically. Many studies have indicated the crosstalk between the tubule and the glomerulus in CKD progression. However, our understanding of the interaction of tubular and glomerular injury remains incomplete. In this study, we applied a meta-analysis approach on the transcriptome of the tubules and glomeruli of CKD patients to identify differentially expressed genes (DEGs) signature. Functional analysis of pathways and Gene Ontology found that tubular DEGs were mainly involved in cell assembly and remodeling, glomerular DEGs in cell proliferation and apoptosis, and overlapping DEGs mainly in immune response. Correlation analysis was performed to identify the associated DEGs in the tubules and glomeruli. Secreted protein comparison and verification experiments indicated that WFDC2 from the tubule could downregulate PEX19 mRNA and protein levels at the glomeruli in diabetic kidney disease (DKD). This study revealed the distinctive pathways of the tubules and glomeruli and identified interacted genes during CKD progression.
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Affiliation(s)
- Lingyun Liu
- Department of Andrology, The First Hospital of Jilin University, Jilin, China
| | - Fuzhe Ma
- Department of Nephrology, The First Hospital of Jilin University, Jilin, China
| | - Yuanyuan Hao
- Department of Urology, The First Hospital of Jilin University, Jilin, China
| | - Zhengzi Yi
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Xiaoxia Yu
- Division of Nephrology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Bo Xu
- Department of Urology, The First Hospital of Jilin University, Jilin, China
| | - Chengguo Wei
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jinghai Hu
- Department of Urology, The First Hospital of Jilin University, Jilin, China
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Kaplan A, Abidi E, Habeichi NJ, Ghali R, Alawasi H, Fakih C, Zibara K, Kobeissy F, Husari A, Booz GW, Zouein FA. Gender-biased kidney damage in mice following exposure to tobacco cigarette smoke: More protection in premenopausal females. Physiol Rep 2021; 8:e14339. [PMID: 31981316 PMCID: PMC6981307 DOI: 10.14814/phy2.14339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Multiple clinical studies documented renal damage in chronic cigarette smokers (CS) irrespective of their age and gender. Premenopausal female smokers are known to exert a certain cardiovascular and renal protection with undefined mechanisms. Given the multiple demographic variables within clinical studies, this experimental study was designed to be the first to assess whether gender‐biased CS‐induced kidney damage truly exists between premenopausal female and age‐matched C57Bl6J male mice when compared to their relative control groups. Following 6 weeks of CS exposure, cardiac function, inflammatory marker production, fibrosis formation, total and glomerular ROS levels, and glomerulotubular homeostasis were assessed in both genders. Although both CS‐exposed male and female mice exhibited comparable ROS fold change relative to their respective control groups, CS‐exposed male mice showed a more pronounced fibrotic deposition, inflammation, and glomerulotubular damage profile. However, the protection observed in CS‐exposed female group was not absolute. CS‐exposed female mice exhibited a significant increase in fibrosis, ROS production, and glomerulotubular alteration but with a pronounced anti‐inflammatory profile when compared to their relative control groups. Although both CS‐exposed genders presented with altered glomerulotubular homeostasis, the alteration phenotype between genders was different. CS‐exposed males showed a significant decrease in Bowman's space along with reduced tubular diameter consistent with an endocrinization pattern of chronic tubular atrophy, suggestive of an advanced stage of glomerulotubular damage. CS‐exposed female group, on the other hand, displayed glomerular hypertrophy with a mild tubular dilatation profile suggestive of an early stage of glomerulotubular damage that generally precedes collapse. In conclusion, both genders are prone to CS‐induced kidney damage with pronounced female protection due to a milder damage slope.
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Affiliation(s)
- Abdullah Kaplan
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Emna Abidi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nada J Habeichi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rana Ghali
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hiam Alawasi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Christina Fakih
- Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Kazem Zibara
- Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ahmad Husari
- Department of Internal Medicine, Respiratory Diseases and Sleep Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - George W Booz
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Fouad A Zouein
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Peritubular Capillary Rarefaction: An Underappreciated Regulator of CKD Progression. Int J Mol Sci 2020; 21:ijms21218255. [PMID: 33158122 PMCID: PMC7662781 DOI: 10.3390/ijms21218255] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 10/29/2020] [Indexed: 12/15/2022] Open
Abstract
Peritubular capillary (PTC) rarefaction is commonly detected in chronic kidney disease (CKD) such as hypertensive nephrosclerosis and diabetic nephropathy. Moreover, PTC rarefaction prominently correlates with impaired kidney function and predicts the future development of end-stage renal disease in patients with CKD. However, it is still underappreciated that PTC rarefaction is a pivotal regulator of CKD progression, primarily because the molecular mechanisms of PTC rarefaction have not been well-elucidated. In addition to the established mechanisms (reduced proangiogenic factors and increased anti-angiogenic factors), recent studies discovered significant contribution of the following elements to PTC loss: (1) prompt susceptibility of PTC to injury, (2) impaired proliferation of PTC, (3) apoptosis/senescence of PTC, and (4) pericyte detachment from PTC. Mainly based on the recent and novel findings in basic research and clinical study, this review describes the roles of the above-mentioned elements in PTC loss and focuses on the major factors regulating PTC angiogenesis, the assessment of PTC rarefaction and its surrogate markers, and an overview of the possible therapeutic agents to mitigate PTC rarefaction during CKD progression. PTC rarefaction is not only a prominent histological characteristic of CKD but also a central driving force of CKD progression.
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Zou J, Yang J, Zhu X, Zhong J, Elshaer A, Matsusaka T, Pastan I, Haase VH, Yang HC, Fogo AB. Stabilization of hypoxia-inducible factor ameliorates glomerular injury sensitization after tubulointerstitial injury. Kidney Int 2020; 99:620-631. [PMID: 33137336 DOI: 10.1016/j.kint.2020.09.031] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/14/2020] [Accepted: 09/17/2020] [Indexed: 12/24/2022]
Abstract
Previously, we found that mild tubulointerstitial injury sensitizes glomeruli to subsequent injury. Here, we evaluated whether stabilization of hypoxia-inducible factor-α (HIF-α), a key regulator of tissue response to hypoxia, ameliorates tubulointerstitial injury and impact on subsequent glomerular injury. Nep25 mice, which express the human CD25 receptor on podocytes under control of the nephrin promotor and develop glomerulosclerosis when a specific toxin is administered were used. Tubulointerstitial injury, evident by week two, was induced by folic acid, and mice were treated with an HIF stabilizer, dimethyloxalylglycine or vehicle from week three to six. Uninephrectomy at week six assessed tubulointerstitial fibrosis. Glomerular injury was induced by podocyte toxin at week seven, and mice were sacrificed ten days later. At week six tubular injury markers normalized but with patchy collagen I and interstitial fibrosis. Pimonidazole staining, a hypoxia marker, was increased by folic acid treatment compared to vehicle while dimethyloxalylglycine stimulated HIF-2α expression and attenuated tubulointerstitial hypoxia. The hematocrit was increased by dimethyloxalylglycine along with downstream effectors of HIF. Tubular epithelial cell injury, inflammation and interstitial fibrosis were improved after dimethyloxalylglycine, with further reduced mortality, interstitial fibrosis, and glomerulosclerosis induced by specific podocyte injury. Thus, our findings indicate that hypoxia contributes to tubular injury and consequent sensitization of glomeruli to injury. Hence, restoring HIFs may blunt this adverse crosstalk of tubules to glomeruli.
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Affiliation(s)
- Jun Zou
- Division of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jaewon Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Division of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Gangwon, South Korea
| | - Xiaoye Zhu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Division of Nephrology, Huashan Hospital, Wudan University, Shanghai, China
| | - Jianyong Zhong
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ahmed Elshaer
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Taiji Matsusaka
- Institute of Medical Science, Tokai University, Isehara, Japan
| | - Ira Pastan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Volker H Haase
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Medicine and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Hai-Chun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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Mertowski S, Lipa P, Morawska I, Niedźwiedzka-Rystwej P, Bębnowska D, Hrynkiewicz R, Grywalska E, Roliński J, Załuska W. Toll-Like Receptor as a Potential Biomarker in Renal Diseases. Int J Mol Sci 2020; 21:ijms21186712. [PMID: 32933213 PMCID: PMC7554805 DOI: 10.3390/ijms21186712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/09/2020] [Accepted: 09/11/2020] [Indexed: 02/08/2023] Open
Abstract
One of the major challenges faced by modern nephrology is the identification of biomarkers associated with histopathological patterns or defined pathogenic mechanisms that may assist in the non-invasive diagnosis of kidney disease, particularly glomerulopathy. The identification of such molecules may allow prognostic subgroups to be established based on the type of disease, thereby predicting response to treatment or disease relapse. Advances in understanding the pathogenesis of diseases, such as membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, IgA (immunoglobulin A) nephropathy, and diabetic nephropathy, along with the progressive development and standardization of plasma and urine proteomics techniques, have facilitated the identification of an increasing number of molecules that may be useful for these purposes. The growing number of studies on the role of TLR (toll-like receptor) receptors in the pathogenesis of kidney disease forces contemporary researchers to reflect on these molecules, which may soon join the group of renal biomarkers and become a helpful tool in the diagnosis of glomerulopathy. In this article, we conducted a thorough review of the literature on the role of TLRs in the pathogenesis of glomerulopathy. The role of TLR receptors as potential marker molecules for the development of neoplastic diseases is emphasized more and more often, as prognostic factors in diseases on several epidemiological backgrounds.
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Affiliation(s)
- Sebastian Mertowski
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
- Correspondence: (S.M.); (P.N.-R.); (E.G.)
| | - Paulina Lipa
- Department of Genetics and Microbiology, Institute of Microbiology and Biotechnology, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19 St., 20-033 Lublin, Poland;
| | - Izabela Morawska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
| | - Paulina Niedźwiedzka-Rystwej
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (D.B.); (R.H.)
- Correspondence: (S.M.); (P.N.-R.); (E.G.)
| | - Dominika Bębnowska
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (D.B.); (R.H.)
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (D.B.); (R.H.)
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
- Correspondence: (S.M.); (P.N.-R.); (E.G.)
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, 20-954 Lublin, Poland;
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Ullah MM, Basile DP. Role of Renal Hypoxia in the Progression From Acute Kidney Injury to Chronic Kidney Disease. Semin Nephrol 2020; 39:567-580. [PMID: 31836039 DOI: 10.1016/j.semnephrol.2019.10.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Over the past 20 years, there has been an increased appreciation of the long-term sequelae of acute kidney injury (AKI) and the potential development of chronic kidney disease (CKD). Several pathophysiologic features have been proposed to mediate AKI to CKD progression including maladaptive alterations in tubular, interstitial, inflammatory, and vascular cells. These alterations likely interact to culminate in the progression to CKD. In this article we focus primarily on evidence of vascular rarefaction secondary to AKI, and the potential mechanisms by which rarefaction occurs in relation to other alterations in tubular and interstitial compartments. We further focus on the potential that rarefaction contributes to renal hypoxia. Consideration of the role of hypoxia in AKI to CKD transition focuses on experimental evidence of persistent renal hypoxia after AKI and experimental maneuvers to evaluate the influence of hypoxia, per se, in progressive disease. Finally, consideration of methods to evaluate hypoxia in patients is provided with the suggestion that noninvasive measurement of renal hypoxia may provide insight into progression in post-AKI patients.
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Affiliation(s)
- Md Mahbub Ullah
- Department of Anatomy, Cell Biology and Physiology, Indiana University, Indianapolis, IN
| | - David P Basile
- Department of Medicine, Division of Nephrology, Indiana University, Indianapolis, IN.
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44
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White S, Lin L, Hu K. NF-κB and tPA Signaling in Kidney and Other Diseases. Cells 2020; 9:E1348. [PMID: 32485860 PMCID: PMC7348801 DOI: 10.3390/cells9061348] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023] Open
Abstract
The activation of the nuclear factor-κB (NF-κB) pathway plays a central role in the initiation and progression of inflammation, which contributes to the pathogenesis and progression of various human diseases including kidney, brain, and other diseases. Tissue plasminogen activator (tPA), a serine protease regulating homeostasis of blood coagulation, fibrinolysis, and matrix degradation, has been shown to act as a cytokine to trigger profound receptor-mediated intracellular events, modulate the NF-κB pathway, and mediate organ dysfunction and injury. In this review, we focus on the current understanding of NF-κB and tPA signaling in the development and progression of kidney disease. Their roles in the nervous and cardiovascular system are also briefly discussed.
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Affiliation(s)
| | - Ling Lin
- Nephrology Research Program, Department of Medicine, Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA;
| | - Kebin Hu
- Nephrology Research Program, Department of Medicine, Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA;
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45
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Luo R, Yang Y, Cheng YC, Chang D, Liu TT, Li YQ, Dai W, Zuo MY, Xu YL, Zhang CX, Ge SW, Xu G. Plasma chemokine CXC motif-ligand 16 as a predictor of renal prognosis in immunoglobulin A nephropathy. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:381. [PMID: 32355825 PMCID: PMC7186753 DOI: 10.21037/atm.2020.02.05] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background There are few non-invasive biomarkers that have been identified to improve the risk stratification of patients with IgA nephropathy (IgAN). CXCL16 has been shown to play a key role as a chemoattractant, adhesion, and fibrosis factor in inflammatory disease. This study evaluated the potential for CXCL16 plasma as a potential biomarker in patients with IgAN. Methods Plasma CXCL16 was measured in 230 patients with renal biopsied IgAN enrolled from 2012 to 2014. The patients were followed for 41.3 months, with a 50% reduction in estimated glomerular filtration rate or end-stage renal disease as endpoints. Results The plasma CXCL16 levels in IgAN patients were strongly correlated with the uric acid, estimated glomerular filtration rate and tubular atrophy/interstitial fibrosis score in multivariate analysis. Furthermore, counts of CD4+ T cells, CD8+ T cells, and CD20+ B cells in renal biopsies of IgAN patients were significantly correlated with the plasma CXCL16 levels, but not CD68+ macrophage. Lastly, we concluded that patients with higher levels of plasma CXCL16 had an increased risk of poor renal outcome compared to those with lower levels. There was no association between the polymorphisms and clinical parameters of CXCL16, including the levels and prognosis of plasma CXCL16. Conclusions Plasma CXCL16 levels were associated with clinical parameters; pathological damage; CD4+ T cell, CD8+ T cell, and CD20+ B cell infiltration in renal tissue; and renal outcome in IgAN patients. Plasma CXCL16 might be a potential prognosis predictor in Chinese IgAN patients.
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Affiliation(s)
- Ran Luo
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yi Yang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yi-Chun Cheng
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dan Chang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ting-Ting Liu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yue-Qiang Li
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei Dai
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Mei-Ying Zuo
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yu-Lin Xu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chun-Xiu Zhang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shu-Wang Ge
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Gang Xu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Luo R, Guo SM, Li YQ, Yang Y, Li ML, Han M, He XF, Ge SW, Xu G. Plasma fractalkine levels are associated with renal inflammation and outcomes in immunoglobulin A nephropathy. Nephrol Dial Transplant 2020; 34:1549-1558. [PMID: 30010903 DOI: 10.1093/ndt/gfy169] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND A recognized noninvasive biomarker to improve risk stratification of immunoglobulin A nephropathy (IgAN) patients is scarce. Fractalkine has been shown to play a key role in glomerular disease as chemoattractant, adhesion and even fibrosis factor. The current study assessed the possibility of plasma fractalkine as a novel biomarker in IgAN patients. METHODS Plasma fractalkine was measured in 229 patients with renal biopsy consistent IgAN from 2012 to 2014, and clinical, pathological and prognostic relationships were analyzed. RESULTS The plasma fractalkine levels in IgAN patients were significantly correlated with the creatinine level and 24-h urine protein by both univariate and multivariate analysis. Mesangial hypercellularity was still significantly correlated with the plasma fractalkine levels even after adjustment for other potential predictor variables by multivariate analysis. In addition, the counts of CD20+ B cells or CD68+ macrophage in renal biopsies of IgAN patients were significantly correlated with the plasma fractalkine levels, but not CD4+ and CD8+ T cells. Finally, we concluded that patients with higher plasma fractalkine levels had higher risk of poor renal outcome compared with those with lower plasma fractalkine levels. No association was observed between the CX3CR1 polymorphisms and clinical parameters including plasma fractalkine levels and prognosis. Recombinant fractalkine induced mesangial cells extracellular matrix synthesis and promoted the migration of microphage cells RAW264.7. CONCLUSIONS Plasma fractalkine levels were associated with creatinine level, 24-h urine protein, mesangial hypercellularity pathological damage, the CD68+ macrophage and CD20+ B cell infiltration in renal tissue and renal outcome in IgAN patients. Plasma fractalkine might be a potential prognosis novel predictor in Chinese patients with IgAN.
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Affiliation(s)
- Ran Luo
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shui-Ming Guo
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yue-Qiang Li
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yi Yang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meng-Lan Li
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Min Han
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiao-Feng He
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shu-Wang Ge
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Gang Xu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Chen Q, Yu J, Rush BM, Stocker SD, Tan RJ, Kim K. Ultrasound super-resolution imaging provides a noninvasive assessment of renal microvasculature changes during mouse acute kidney injury. Kidney Int 2020; 98:355-365. [PMID: 32600826 DOI: 10.1016/j.kint.2020.02.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 01/22/2020] [Accepted: 02/06/2020] [Indexed: 12/26/2022]
Abstract
Acute kidney injury (AKI) is a risk factor for the development of chronic kidney disease (CKD). One mechanism for this phenomenon is renal microvascular rarefaction and subsequent chronic impairment in perfusion. However, diagnostic tools to monitor the renal microvasculature in a noninvasive and quantitative manner are still lacking. Ultrasound super-resolution imaging is an emerging technology that can identify microvessels with unprecedented resolution. Here, we applied this imaging technique to identify microvessels in the unilateral ischemia-reperfusion injury mouse model of AKI-to-CKD progression in vivo. Kidneys from 21 and 42 day post- ischemia-reperfusion injury, the contralateral uninjured kidneys, and kidneys from sham-operated mice were examined by ultrasound super-resolution and histology. Renal microvessels were successfully identified by this imaging modality with a resolution down to 32 μm. Renal fibrosis was observed in all kidneys with ischemia-reperfusion injury and was associated with a significant reduction in kidney size, cortical thickness, relative blood volume, and microvascular density as assessed by this imaging. Tortuosity of the cortical microvasculature was also significantly increased at 42 days compared to sham. These vessel density measurements correlated significantly with CD31 immunohistochemistry (R2=0.77). Thus, ultrasound super-resolution imaging provides unprecedented resolution and is capable of noninvasive quantification of renal vasculature changes associated with AKI-to-CKD progression in mice. Hence, this technique could be a promising diagnostic tool for monitoring progressive kidney disease.
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Affiliation(s)
- Qiyang Chen
- Department of Bioengineering, University of Pittsburgh School of Engineering, Pittsburgh, Pennsylvania, USA; Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, Heart and Vascular Institute, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Jaesok Yu
- Department of Bioengineering, University of Pittsburgh School of Engineering, Pittsburgh, Pennsylvania, USA; Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, Heart and Vascular Institute, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Brittney M Rush
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Sean D Stocker
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Roderick J Tan
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
| | - Kang Kim
- Department of Bioengineering, University of Pittsburgh School of Engineering, Pittsburgh, Pennsylvania, USA; Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, Heart and Vascular Institute, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; McGowan Institute of Regenerative Medicine, University of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Department of Mechanical Engineering and Materials Science, University of Pittsburgh School of Engineering, Pittsburgh, Pennsylvania, USA.
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Abstract
PURPOSE OF REVIEW Preclinical data suggests that transforming growth factor-β (TGF-β) is arguably the most potent profibrotic growth factor in kidney injury. Despite this, recent clinical trials targeting TGF-β have been disappointing. These negative studies suggest that TGF-β signaling in the injured kidney might be more complicated than originally thought. This review examines recent studies that expand our understanding of how this pleiotropic growth factor affects renal injury. RECENT FINDINGS There are recent studies showing new mechanisms whereby TGF-β can mediate injury (e.g. epigenetic effects, macrophage chemoattractant). However, more significant are the increasing reports on cross-talk between TGF-β signaling and other pathways relevant to renal injury such as Wnt/β-catenin, YAP/TAZ (transcriptional coactivator with PDZ-binding motif), and klotho/FGF23. TGF-β clearly alters the response to injury, not just by direct transcriptional changes on target cells, but also through effects on other signaling pathways. In T cells and tubular epithelial cells, some of these TGF-β-mediated changes are potentially beneficial. SUMMARY It is unlikely that inhibition of TGF-β per se will be a successful antifibrotic strategy, but a better understanding of TGF-β's actions may reveal promising downstream targets or modulators of signaling to target therapeutically for chronic kidney disease.
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Urinary biomarkers of latent inflammation and fibrosis in children with vesicoureteral reflux. Int Urol Nephrol 2019; 52:603-610. [PMID: 31832877 DOI: 10.1007/s11255-019-02357-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 12/05/2019] [Indexed: 12/28/2022]
Abstract
PURPOSE To investigate the urinary levels of TGF-β1, VEGF, and MCP-1 as potential biomarkers of latent inflammation and fibrosis in the kidney before and 6 months after correction of vesicoureteral reflux (VUR) in children. METHODS A total of 88 patients (mean age 26 months) with VUR were divided into three groups: group A-patients with grades II-III VUR, conservative treatment; group B-patients with grades III-V VUR, endoscopic correction of VUR; group C-patients with grades III-V VUR, ureteral reimplantation after failed endoscopic correction. Control group included 20 healthy children. Biomarker levels were measured by ELISA. 99mTc-DMSA scintigraphy and renal histology were performed if possible. RESULTS At admission, TGF-β1 was close to control in all study groups, VEGF increased with severity of the disease, and MCP-1 increased in group C. Six months after correction of VUR, despite clinical and laboratory improvement, TGF-β1 and MCP-1 increased while VEGF decreased compared to the admission values in all groups; no amelioration of renal scarring was detected either by 99mTc-DMSA scintigraphy or renal histology. CONCLUSION The results support our hypothesis that successful correction of VUR is not sufficient to stop or reduce the latent inflammatory and fibrotic processes that have already started in the kidney regardless of the reflux grade and treatment option. Measuring the urinary levels of TGF-β1, VEGF, and MCP-1 may aid in the development of non-invasive, pathophysiologically relevant approach to diagnosis and monitoring of kidney injury and fibrosis in children with VUR.
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Basile DP. The case for capillary rarefaction in the AKI to CKD progression: insights from multiple injury models. Am J Physiol Renal Physiol 2019; 317:F1253-F1254. [DOI: 10.1152/ajprenal.00468.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- David P. Basile
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana
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