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Al Tuhaifi T, Zhong J, Yang HC, Fogo AB. Effects of Dipeptidyl Peptidase-4 Inhibitor and Angiotensin-Converting Enzyme Inhibitor on Experimental Diabetic Kidney Disease. J Transl Med 2024; 104:100305. [PMID: 38109999 PMCID: PMC10922867 DOI: 10.1016/j.labinv.2023.100305] [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: 02/11/2023] [Revised: 11/08/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and worldwide. Proteinuria is a major marker of the severity of injury. Dipeptidyl peptidase-4 inhibitor (DPP-4I) increases incretin-related insulin production and is, therefore, used to treat diabetes. We investigated whether DPP4I could have direct effect on kidney independent of its hypoglycemic activity. We, therefore, tested the effects of DPP4I with or without angiotensin-converting enzyme inhibitor (ACEI) on the progression of diabetic nephropathy and albuminuria in a murine model of DKD. eNOS-/-db/db mice were randomized to the following groups at age 10 weeks and treated until sacrifice: baseline (sacrificed at week 10), untreated control, ACEI, DPP4I, and combination of DPP4I and ACEI (Combo, sacrificed at week 18). Systemic parameters and urine albumin-creatinine ratio were assessed at baseline, weeks 14, and 18. Kidney morphology, glomerular filtration rate (GFR), WT-1, a marker for differentiated podocytes, podoplanin, a marker of foot process integrity, glomerular collagen IV, and alpha-smooth muscle actin were assessed at the end of the study. All mice had hyperglycemia and proteinuria at study entry at week 10. Untreated control mice had increased albuminuria, progression of glomerular injury, and reduced GFR at week 18 compared with baseline. DPP4I alone reduced blood glucose and kidney DPP-4 activity but failed to protect against kidney injury compared with untreated control. ACEI alone and combination groups showed significantly reduced albuminuria and glomerular injury, and maintained GFR and WT-1+ cells. Only the combination group had significantly less glomerular collagen IV deposition and more podoplanin preservation than the untreated control. DPP-4I alone does not decrease the progression of kidney injury in the eNOS-/-db/db mouse model, suggesting that targeting only hyperglycemia is not an optimal treatment strategy for DKD. Combined DPP-4I with ACEI added more benefit to reducing the glomerular matrix.
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Affiliation(s)
- Tareq Al Tuhaifi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Nephrology Clinical Trials Center, Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jianyong Zhong
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hai-Chun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Ahmed S, de Vries JC, Lu J, Stuart MHV, Mihăilă SM, Vernooij RWM, Masereeuw R, Gerritsen KGF. Animal Models for Studying Protein-Bound Uremic Toxin Removal-A Systematic Review. Int J Mol Sci 2023; 24:13197. [PMID: 37686004 PMCID: PMC10487432 DOI: 10.3390/ijms241713197] [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: 07/25/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional dialysis techniques are unable to efficiently remove PBUTs due to their plasma protein binding. Therefore, novel approaches are being developed, but these require validation in animals before clinical trials can begin. We conducted a systematic review to document PBUT concentrations in various models and species. The search strategy returned 1163 results for which abstracts were screened, resulting in 65 full-text papers for data extraction (rats (n = 41), mice (n = 17), dogs (n = 3), cats (n = 4), goats (n = 1), and pigs (n = 1)). We performed descriptive and comparative analyses on indoxyl sulfate (IS) concentrations in rats and mice. The data on large animals and on other PBUTs were too heterogeneous for pooled analysis. Most rodent studies reported mean uremic concentrations of plasma IS close to or within the range of those during kidney failure in humans, with the highest in tubular injury models in rats. Compared to nephron loss models in rats, a greater rise in plasma IS compared to creatinine was found in tubular injury models, suggesting tubular secretion was more affected than glomerular filtration. In summary, tubular injury rat models may be most relevant for the in vivo validation of novel PBUT-lowering strategies for kidney failure in humans.
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Affiliation(s)
- Sabbir Ahmed
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; (S.A.); (J.L.); (S.M.M.); (R.M.)
| | - Joost C. de Vries
- Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.C.d.V.); (M.H.V.S.); (R.W.M.V.)
| | - Jingyi Lu
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; (S.A.); (J.L.); (S.M.M.); (R.M.)
| | - Milan H. Verrijn Stuart
- Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.C.d.V.); (M.H.V.S.); (R.W.M.V.)
| | - Silvia M. Mihăilă
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; (S.A.); (J.L.); (S.M.M.); (R.M.)
| | - Robin W. M. Vernooij
- Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.C.d.V.); (M.H.V.S.); (R.W.M.V.)
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; (S.A.); (J.L.); (S.M.M.); (R.M.)
| | - Karin G. F. Gerritsen
- Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.C.d.V.); (M.H.V.S.); (R.W.M.V.)
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Tanaka S, Wakui H, Azushima K, Tsukamoto S, Yamaji T, Urate S, Suzuki T, Abe E, Taguchi S, Yamada T, Kobayashi R, Kanaoka T, Kamimura D, Kinguchi S, Takiguchi M, Funakoshi K, Yamashita A, Ishigami T, Tamura K. Effects of a High-Protein Diet on Kidney Injury under Conditions of Non-CKD or CKD in Mice. Int J Mol Sci 2023; 24:ijms24097778. [PMID: 37175483 PMCID: PMC10177820 DOI: 10.3390/ijms24097778] [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: 03/02/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 05/15/2023] Open
Abstract
Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects.
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Affiliation(s)
- Shohei Tanaka
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Kengo Azushima
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Shunichiro Tsukamoto
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Takahiro Yamaji
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Shingo Urate
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Toru Suzuki
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Eriko Abe
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Shinya Taguchi
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Takayuki Yamada
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA
| | - Ryu Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Tomohiko Kanaoka
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Daisuke Kamimura
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Sho Kinguchi
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Masahito Takiguchi
- Department of Neuroanatomy, School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Kengo Funakoshi
- Department of Neuroanatomy, School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Akio Yamashita
- Department of Investigative Medicine, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishiharacho, Okinawa 903-0215, Japan
| | - Tomoaki Ishigami
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
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Wang J, Matsushita K, Zhong J, Ma LJ, Yang HC, Fogo AB. Low-Dose Erythropoietin Amplifies Beneficial Effects of Angiotensin II Blockade on Glomerulosclerosis. J Transl Med 2023; 103:100015. [PMID: 37039147 PMCID: PMC11610902 DOI: 10.1016/j.labinv.2022.100015] [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: 10/18/2021] [Revised: 09/02/2022] [Accepted: 09/20/2022] [Indexed: 01/11/2023] Open
Abstract
Exogenous erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). Concerns about the possible adverse effect of EPO on the progression of CKD have been raised owing to nonerythroid cell effects. We investigated the effects of low-dose EPO, independent of correcting anemia, on existing glomerulosclerosis. Adult mice underwent 5/6 nephrectomy and were randomized into the following 4 groups at week 8 after surgery: vehicle (VEH), losartan (angiotensin II type 1 receptor blocker [ARB]), darbepoetin-α (DA), or combination (DA+ARB). Four weeks later, mice were euthanized, followed by evaluation of renal structure and function. Glomerular endothelial cells and podocytes were cultured to evaluate the effects of DA on cell migration, apoptosis, and Akt signaling. ARB reduced blood pressure, albuminuria, and the level of serum creatinine and increased hematocrit compared with VEH, whereas low-dose DA only reduced the level of serum creatinine. Combination treatment showed a trend to increase hematocrit and survival compared with ARB alone. Combination treatment but not ARB alone significantly reduced the progression of glomerulosclerosis compared with VEH. Low-dose DA resulted in more preserved glomerular and peritubular capillary endothelial cells with increased p-Akt and even further endothelial cell preservation in combination with ARB. In cultured glomerular endothelial cells, angiotensin II induced more apoptosis, reduced migration, and decreased p-Flk1, a receptor for the proangiogenic vascular endothelial growth factor. DA counteracted these injuries and increased p-Akt, a key factor in angiogenesis and cell survival. DA also protected cultured podocytes against transforming growth factor β-induced apoptosis and synaptopodin loss. Low-dose EPO directly protects glomerular and peritubular endothelial cells via Akt phosphorylation. Therefore, treatment using a combination of low-dose EPO and ARB results in less progression of glomerulosclerosis in an experimental CKD model.
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Affiliation(s)
- Jiayi Wang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Keizo Matsushita
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jianyong Zhong
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Li-Jun Ma
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hai-Chun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Badal SS, Al Tuhaifi T, Yu YF, Lopez D, Plato CT, Joly K, Breckenridge DG, Yang HC, Liles JT, Fogo AB. Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model. KIDNEY360 2022; 3:1169-1182. [PMID: 35919527 PMCID: PMC9337896 DOI: 10.34067/kid.0001032022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/05/2022] [Indexed: 01/12/2023]
Abstract
Background Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with CKD, there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the nondiabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril. Methods Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib plus enalapril), and untreated controls. Serum creatinine, systolic BP (SBP), and urinary albumin were measured at intervals. Animals were euthanized at week 12 for histologic, biochemical, and molecular analyses. Results All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8 to 12 reduced SBP versus controls, decreased albuminuria, and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, whereas selonsertib treatment reduced apoptosis and podocyte loss. RNA-seq revealed that combined treatment influenced pathways related to extracellular matrix and wound healing. Conclusions Selonsertib targets a novel, nonhemodynamic pathway in CKD. Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.
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Affiliation(s)
| | - Tareq Al Tuhaifi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ya-Fen Yu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Fourth Hospital, Wuxi, Anhui, China
| | - David Lopez
- Gilead Sciences, Inc., Foster City, California
| | | | | | | | - Hai-Chun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Agnes B. Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
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Zhu X, Gao D, Albertazzi V, Zhong J, Ma LJ, Du L, Shyr Y, Kon V, Yang HC, Fogo AB. Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker. Int J Mol Sci 2022; 23:6018. [PMID: 35682697 PMCID: PMC9181646 DOI: 10.3390/ijms23116018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/18/2022] [Accepted: 05/23/2022] [Indexed: 12/10/2022] Open
Abstract
We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.
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Affiliation(s)
- Xuejing Zhu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha 410011, China;
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (D.G.); (V.A.); (J.Z.); (L.-J.M.); (H.-C.Y.)
| | - Dan Gao
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (D.G.); (V.A.); (J.Z.); (L.-J.M.); (H.-C.Y.)
- Department of Nephrology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Vittorio Albertazzi
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (D.G.); (V.A.); (J.Z.); (L.-J.M.); (H.-C.Y.)
- Unit of Nephrology and Dialysis, “Guglielmo da Saliceto” AUSL Piacenza Hospital, Via Taverna 49, 29100 Piacenza, Italy
| | - Jianyong Zhong
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (D.G.); (V.A.); (J.Z.); (L.-J.M.); (H.-C.Y.)
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Li-Jun Ma
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (D.G.); (V.A.); (J.Z.); (L.-J.M.); (H.-C.Y.)
| | - Liping Du
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (L.D.); (Y.S.)
| | - Yu Shyr
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (L.D.); (Y.S.)
| | - Valentina Kon
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Hai-Chun Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (D.G.); (V.A.); (J.Z.); (L.-J.M.); (H.-C.Y.)
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Agnes B. Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (D.G.); (V.A.); (J.Z.); (L.-J.M.); (H.-C.Y.)
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
- Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Kuźmiuk-Glembin I, Heleniak Z, Pięta R, Głyda M, Lizakowski S, Renke M, Konopa J, Chamienia A, Biedunkiewicz B, Rutkowski B, Tylicki L, Dębska-Ślizień A. Short-term Effects of Losartan on Cardiovascular Risk and Allograft Injury Biomarkers in Kidney Transplant Recipients. Transplant Proc 2022; 54:981-988. [PMID: 35346485 DOI: 10.1016/j.transproceed.2022.02.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/03/2022] [Accepted: 02/18/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND There is a controversy over the renoprotective and cardioprotective effects of renin-angiotensin-aldosterone system blockade in kidney transplant recipients (KTRs). The aim of the study was to evaluate the short-term effects of losartan on allograft injury, cardiovascular risk biomarkers and safety of the treatment in KTRs. METHODS An interim analysis of a prospective, open, multicenter, controlled clinical trial CELART (Cardiovascular Effects of Losartan After Renal Transplantation) was performed. KTRs were allocated to losartan (L) 50 to 100 mg or standard hypotensive treatment (ST) group to reach target blood pressure (BP) <140/90 mm Hg. The short-term effects of the therapy were evaluated after 6 months: estimated glomerular filtration rate (eGFR), albuminuria, the intrarenal fibrosis biomarkers: urine excretion of transforming growth factor β-1 (TGFβ-1) and procollagen type III amino terminal propeptide (PIIINP), cardiac biomarker: serum concentration of N-terminal-pro-B-type natriuretic peptide (NT-proBNP), 24-hour ambulatory BP measurement, and hemoglobin and potassium concentrations. RESULTS At baseline the groups did not differ with respect to age, primary nephropathy, comorbidity, immunosuppressive therapy, albuminuria, and graft function. A total of 61 (L group) and 73 (ST group) patients reached the target BP and completed protocol at 6 months. After 6 months of therapy there were no significant differences in changes of eGFR, albuminuria, hemoglobin and potassium concentrations, urine excretion of PIIINP, and TGFβ-1 between groups. There was a trend in the L group to decrease the concentration of serum NT-proBNP. CONCLUSIONS Losartan shows minimal adverse effects and no influence on graft function and biomarkers of graft fibrosis. It may have a positive effect on cardiovascular risk in KTRs. Further interim analyses of the CELART study will be conducted.
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Affiliation(s)
- Izabella Kuźmiuk-Glembin
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Zbigniew Heleniak
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Renata Pięta
- Department of Transplantology and Surgery, District Public Hospital, Poznań, Poland
| | - Maciej Głyda
- Department of Transplantology and Surgery, District Public Hospital, Poznań, Poland; Collegium Medicum In Bydgoszcz, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Sławomir Lizakowski
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Marcin Renke
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland; Division of Occupational, Metabolic, and Internal Diseases, National Centre for Maritime Medicine, Medical University of Gdańsk, Gdynia, Poland
| | - Joanna Konopa
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Andrzej Chamienia
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Bogdan Biedunkiewicz
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Bolesław Rutkowski
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Leszek Tylicki
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland.
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Ravaglia F, Melica ME, Angelotti ML, De Chiara L, Romagnani P, Lasagni L. The Pathology Lesion Patterns of Podocytopathies: How and why? Front Cell Dev Biol 2022; 10:838272. [PMID: 35281116 PMCID: PMC8907833 DOI: 10.3389/fcell.2022.838272] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/07/2022] [Indexed: 11/13/2022] Open
Abstract
Podocytopathies are a group of proteinuric glomerular disorders driven by primary podocyte injury that are associated with a set of lesion patterns observed on kidney biopsy, i.e., minimal changes, focal segmental glomerulosclerosis, diffuse mesangial sclerosis and collapsing glomerulopathy. These unspecific lesion patterns have long been considered as independent disease entities. By contrast, recent evidence from genetics and experimental studies demonstrated that they represent signs of repeated injury and repair attempts. These ongoing processes depend on the type, length, and severity of podocyte injury, as well as on the ability of parietal epithelial cells to drive repair. In this review, we discuss the main pathology patterns of podocytopathies with a focus on the cellular and molecular response of podocytes and parietal epithelial cells.
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Affiliation(s)
| | - Maria Elena Melica
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Maria Lucia Angelotti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Letizia De Chiara
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Paola Romagnani
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Nephrology Unit, Meyer Children’s Hospital, Florence, Italy
| | - Laura Lasagni
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
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9
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Bovée DM, Ren L, Uijl E, Clahsen-van Groningen MC, van Veghel R, Garrelds IM, Domenig O, Poglitsch M, Zlatev I, Kim JB, Huang S, Melton L, Lu X, Hoorn EJ, Foster D, Danser AHJ. Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease. Hypertension 2021; 77:1600-1612. [PMID: 33719507 DOI: 10.1161/hypertensionaha.120.16876] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Dominique M Bovée
- Division of Vascular Medicine and Pharmacology (D.M.B., L.R., E.U., R.v.V., I.M.G., A.H.J.D.), Erasmus MC, University Medical Center Rotterdam, the Netherlands.,Division of Nephrology and Transplantation, Department of Internal Medicine (D.M.B., E.U., E.J.H.), Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - Liwei Ren
- Division of Vascular Medicine and Pharmacology (D.M.B., L.R., E.U., R.v.V., I.M.G., A.H.J.D.), Erasmus MC, University Medical Center Rotterdam, the Netherlands.,Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital) of Jinan University, China (L.R.)
| | - Estrellita Uijl
- Division of Vascular Medicine and Pharmacology (D.M.B., L.R., E.U., R.v.V., I.M.G., A.H.J.D.), Erasmus MC, University Medical Center Rotterdam, the Netherlands.,Division of Nephrology and Transplantation, Department of Internal Medicine (D.M.B., E.U., E.J.H.), Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | | | - Richard van Veghel
- Division of Vascular Medicine and Pharmacology (D.M.B., L.R., E.U., R.v.V., I.M.G., A.H.J.D.), Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - Ingrid M Garrelds
- Division of Vascular Medicine and Pharmacology (D.M.B., L.R., E.U., R.v.V., I.M.G., A.H.J.D.), Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | | | | | - Ivan Zlatev
- Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., S.H., L.M., D.F.)
| | - Jae B Kim
- Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., S.H., L.M., D.F.)
| | - Stephen Huang
- Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., S.H., L.M., D.F.)
| | - Lauren Melton
- Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., S.H., L.M., D.F.)
| | - Xifeng Lu
- Department of Physiology, AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen University, China (X.L.)
| | - Ewout J Hoorn
- Division of Nephrology and Transplantation, Department of Internal Medicine (D.M.B., E.U., E.J.H.), Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - Don Foster
- Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., S.H., L.M., D.F.)
| | - A H Jan Danser
- Division of Vascular Medicine and Pharmacology (D.M.B., L.R., E.U., R.v.V., I.M.G., A.H.J.D.), Erasmus MC, University Medical Center Rotterdam, the Netherlands
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10
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Effects of exercise training on renal interstitial fibrosis and renin-angiotensin system in rats with chronic renal failure. J Hypertens 2020; 39:143-152. [PMID: 32833922 DOI: 10.1097/hjh.0000000000002605] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To clarify the mechanisms of the renal protective effects of exercise training, we examined the effects of exercise training on the renal interstitial fibrosis and renin-angiotensin system (RAS) in rats with chronic renal failure. METHODS Six-week-old male Sprague-Dawley rats were divided into three groups: sham operation; 5/6 nephrectomy + sedentary; 5/6 nephrectomy + exercise training. The 5/6 nephrectomy + exercise training group underwent treadmill running (20 m/min, 60 min/day, 5 days/week). After 12 weeks, renal function, histology and protein expression of collagen type I, transforming growth factor-β1 (TGF-β1), matrix metalloproteinase (MMP), tissue inhibitors of metalloproteinase (TIMP) and RAS components in the renal cortex were examined. RESULTS Exercise training ameliorated the 5/6 nephrectomy-induced hypertension, proteinuria, renal dysfunction, glomerular sclerosis and renal interstitial fibrosis. 5/6 Nephrectomy increased the expression of collagen type I, TGF-β1, MMP-2, MMP-9, TIMP-1, angiotensinogen, angiotensin-converting enzyme (ACE), (pro)renin receptor and angiotensin II type 1 receptor, and exercise training inhibited the 5/6 nephrectomy-increased expression of collagen type I, TGF-β1, TIMP-1, angiotensinogen and ACE expressions. 5/6 Nephrectomy decreased the expression of renin, ACE2, angiotensin II type 2 receptor and Mas receptor, and exercise training inhibited the 5/6 nephrectomy-decreased expressions. CONCLUSION These results indicated that exercise training attenuates the progression of glomerular sclerosis and renal interstitial fibrosis in chronic renal failure rats. The renal protective effects of exercise training may be mediated by ameliorating the renal collagen turnover and the exacerbation of renal RAS.
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11
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OGT knockdown counteracts high phosphate-induced vascular calcification in chronic kidney disease through autophagy activation by downregulating YAP. Life Sci 2020; 261:118121. [PMID: 32693242 DOI: 10.1016/j.lfs.2020.118121] [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: 02/20/2020] [Revised: 06/29/2020] [Accepted: 07/15/2020] [Indexed: 02/05/2023]
Abstract
AIMS Pathological vascular calcification (VC), a major risk factor for cardiovascular mortality, is a highly prevalent finding in patients with chronic kidney disease (CKD). We previously analyzed several pathways protecting against high phosphate-induced VC through induction of autophagy. Here, we explored how O-GlcNAc transferase (OGT) affected high phosphate-induced VC of CKD though mediation of autophagy. MAIN METHODS In the rats with CKD induced by 5/6 nephrectomy, the VC process was accelerated by a high phosphate diet. The calcification of vascular smooth muscle cells (VSMCs) was induced by high phosphate treatment. We then experimentally tested the effect of OGT on high phosphate-induced VC by conducting loss-of-function experiments. Co-immunoprecipitation and GST pull-down assays were performed to evaluate interaction between OGT and Yes-associated protein (YAP). In mechanistic studies of this pathway, we measured autophagy protein expression and autophagosome formation, as well as calcium deposition and calcium content in VSMCs and in vivo in response to altered expression of OGT and/or YAP. KEY FINDINGS OGT was up-regulated in high phosphate-induced VC models in vitro and in vivo. High phosphate-induced calcification in the rat aorta and VSMCs were suppressed by OGT silencing. OGT promoted the glycosylation of YAP to enhance its stability. Importantly, over-expressing YAP reduced autophagy and OGT expedited high phosphate-induced VC by inhibiting autophagy through upregulation of YAP. SIGNIFICANCE OGT silencing downregulated YAP to induce autophagy activation, thus suppressing high phosphate-induced VC, which highlighted a promising preventive target against high phosphate-induced VC in CKD.
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12
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Chaves LD, McSkimming DI, Bryniarski MA, Honan AM, Abyad S, Thomas SA, Wells S, Buck M, Sun Y, Genco RJ, Quigg RJ, Yacoub R. Chronic kidney disease, uremic milieu, and its effects on gut bacterial microbiota dysbiosis. Am J Physiol Renal Physiol 2018; 315:F487-F502. [PMID: 29693447 PMCID: PMC6172581 DOI: 10.1152/ajprenal.00092.2018] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/19/2018] [Accepted: 04/19/2018] [Indexed: 12/12/2022] Open
Abstract
Several lines of evidence suggest that gut bacterial microbiota is altered in patients with chronic kidney disease (CKD), though the mechanism of which this dysbiosis takes place is not well understood. Recent studies delineated changes in gut microbiota in both CKD patients and experimental animal models using microarray chips. We present 16S ribosomal RNA gene sequencing of both stool pellets and small bowel contents of C57BL/6J mice that underwent a remnant kidney model and establish that changes in microbiota take place in the early gastrointestinal tract. Increased intestinal urea concentration has been hypothesized as a leading contributor to dysbiotic changes in CKD. We show that urea transporters (UT)-A and UT-B mRNA are both expressed throughout the whole gastrointestinal tract. The noted increase in intestinal urea concentration appears to be independent of UTs' expression. Urea supplementation in drinking water resulted in alteration in bacterial gut microbiota that is quite different than that seen in CKD. This indicates that increased intestinal urea concentration might not fully explain the CKD- associated dysbiosis.
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Affiliation(s)
- Lee D Chaves
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Daniel I McSkimming
- Genome, Environment, and Microbiome Community of Excellence, University at Buffalo , Buffalo, New York
| | - Mark A Bryniarski
- Department of Pharmaceutical Sciences, University at Buffalo School of Pharmacy and Pharmaceutical Sciences , Buffalo, New York
| | - Amanda M Honan
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Sham Abyad
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Shruthi A Thomas
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Steven Wells
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Michael Buck
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Yijun Sun
- Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Robert J Genco
- Department of Oral Biology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Richard J Quigg
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
| | - Rabi Yacoub
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York
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13
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Liles JT, Corkey BK, Notte GT, Budas GR, Lansdon EB, Hinojosa-Kirschenbaum F, Badal SS, Lee M, Schultz BE, Wise S, Pendem S, Graupe M, Castonguay L, Koch KA, Wong MH, Papalia GA, French DM, Sullivan T, Huntzicker EG, Ma FY, Nikolic-Paterson DJ, Altuhaifi T, Yang H, Fogo AB, Breckenridge DG. ASK1 contributes to fibrosis and dysfunction in models of kidney disease. J Clin Invest 2018; 128:4485-4500. [PMID: 30024858 DOI: 10.1172/jci99768] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 07/13/2018] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.
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Affiliation(s)
| | | | | | | | | | | | | | - Michael Lee
- Gilead Sciences, Foster City, California, USA
| | | | - Sarah Wise
- Gilead Sciences, Foster City, California, USA
| | | | | | | | - Keith A Koch
- Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA
| | | | | | | | | | | | - Frank Y Ma
- Department of Nephrology and Monash University Centres for Inflammatory Diseases, Monash Medical Centre, Clayton, Victoria, Australia
| | - David J Nikolic-Paterson
- Department of Nephrology and Monash University Centres for Inflammatory Diseases, Monash Medical Centre, Clayton, Victoria, Australia
| | - Tareq Altuhaifi
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Haichun Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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14
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Chang CT, Shen MY, Lee AS, Wang CC, Chen WY, Chang CM, Chang KC, Stancel N, Chen CH. Electronegative low-density lipoprotein increases the risk of ischemic lower-extremity peripheral artery disease in uremia patients on maintenance hemodialysis. Sci Rep 2017; 7:4654. [PMID: 28680087 PMCID: PMC5498573 DOI: 10.1038/s41598-017-04063-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 05/08/2017] [Indexed: 12/31/2022] Open
Abstract
Electronegative low-density lipoprotein (LDL) has been shown to increase coronary artery disease risk in hemodialysis patients, but its effect on the risk of peripheral artery disease (PAD) remains unclear. We separated plasma LDL from 90 uremia patients undergoing hemodialysis into 5 subfractions (L1-L5) according to charge by using fast-protein liquid chromatography with an anion-exchange column and examined the distribution of L5-the most electronegative LDL subfraction-in total LDL (i.e. L5%). During a 5-year period, we followed up with these patients until the occurrence of ischemic lower-extremity PAD. During the follow-up period, ischemic lower-extremity PAD developed in 24.4% of hemodialysis patients. L5% was higher in hemodialysis patients in whom ischemic lower-extremity PAD occurred (3.03% [IQR, 2.36-4.54], n = 22) than in hemodialysis patients in whom PAD did not occur (1.13% [IQR, 0.90-1.83], n = 68) (p < 0.001). Furthermore, L5% significantly increased the adjusted hazard ratio of ischemic lower-extremity PAD (1.54 [95% CI, 1.14-2.10]) (p = 0.005). Flow-mediated dilation was negatively associated with L5% (p < 0.001). Additionally, in vivo experiments from mice showed that L5 compromised endothelium-dependent vascular relaxation through a nitric oxide-related mechanism. Our findings indicate that increased L5% may be associated with the occurrence of ischemic lower-extremity PAD in hemodialysis patients.
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Affiliation(s)
- Chiz-Tzung Chang
- Division of Nephrology, China Medical University Hospital (CMUH), Taichung, Taiwan.,Cardiovascular Research Laboratory, CMUH, Taichung, Taiwan.,College of Medicine, China Medical University (CMU), Taichung, Taiwan
| | - Ming-Yi Shen
- Graduate Institute of Clinical Medical Science, CMU, Taichung, Taiwan.,Department of Medical Research, CMUH, Taichung, Taiwan
| | - An-Sean Lee
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Chun-Cheng Wang
- Cardiovascular Research Laboratory, CMUH, Taichung, Taiwan.,College of Medicine, China Medical University (CMU), Taichung, Taiwan.,Graduate Institute of Clinical Medical Science, CMU, Taichung, Taiwan
| | - Wei-Yu Chen
- Cardiovascular Research Laboratory, CMUH, Taichung, Taiwan
| | | | - Kuan-Cheng Chang
- Cardiovascular Research Laboratory, CMUH, Taichung, Taiwan.,College of Medicine, China Medical University (CMU), Taichung, Taiwan
| | - Nicole Stancel
- Vascular and Medicinal Research, Texas Heart Institute, Houston, TX, United States
| | - Chu-Huang Chen
- Vascular and Medicinal Research, Texas Heart Institute, Houston, TX, United States. .,Lipid Science and Aging Research Center, Kaohsiung Medical University (KMU), Kaohsiung, Taiwan. .,Center for Lipid Biosciences, KMU Hospital, Kaohsiung, Taiwan.
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15
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Differential renal effects of candesartan at high and ultra-high doses in diabetic mice-potential role of the ACE2/AT2R/Mas axis. Biosci Rep 2016; 36:BSR20160344. [PMID: 27612496 PMCID: PMC5091470 DOI: 10.1042/bsr20160344] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 09/06/2016] [Indexed: 12/22/2022] Open
Abstract
High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes.
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16
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Elmas O, Erbas O, Yigitturk G. The efficacy of Aesculus hippocastanum seeds on diabetic nephropathy in a streptozotocin-induced diabetic rat model. Biomed Pharmacother 2016; 83:392-396. [DOI: 10.1016/j.biopha.2016.06.055] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/28/2016] [Accepted: 06/29/2016] [Indexed: 12/20/2022] Open
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17
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D'Elia JA, Bayliss G, Gleason RE, Weinrauch LA. Cardiovascular-renal complications and the possible role of plasminogen activator inhibitor: a review. Clin Kidney J 2016; 9:705-12. [PMID: 27679717 PMCID: PMC5036907 DOI: 10.1093/ckj/sfw080] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 07/20/2016] [Indexed: 12/14/2022] Open
Abstract
Since angiotensin increases the expression of plasminogen activator inhibitor (PAI), mechanisms associated with an actively functioning renin–angiotensin–aldosterone system can be expected to be associated with increased PAI-1 expression. These mechanisms are present not only in common conditions resulting in glomerulosclerosis associated with aging, diabetes or genetic mutations, but also in autoimmune disease (like scleroderma and lupus), radiation injury, cyclosporine toxicity, allograft nephropathy and ureteral obstruction. While the renin–angiotensin–aldosterone system and growth factors, such as transforming growth factor-beta (TGF-β), are almost always part of the process, there are rare experimental observations of PAI-1 expression without their interaction. Here we review the literature on PAI-1 and its role in vascular, fibrotic and oxidative injury as well as work suggesting potential areas of intervention in the pathogenesis of multiple disorders.
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Affiliation(s)
- John A D'Elia
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - George Bayliss
- Division ofKidney Diseases and Hypertension, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA; The Miriam Hospital, Providence, RI, USA; Alpert Medical School, Brown University, Providence, RI, USA
| | - Ray E Gleason
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; EP Joslin Research Laboratory, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
| | - Larry A Weinrauch
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; EP Joslin Research Laboratory, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
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18
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Mazzinghi B, Romagnani P, Lazzeri E. Biologic modulation in renal regeneration. Expert Opin Biol Ther 2016; 16:1403-1415. [DOI: 10.1080/14712598.2016.1219336] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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19
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Yim HE, Yoo KH, Bae IS, Hong YS. Early Treatment With Enalapril and Later Renal Injury in Programmed Obese Adult Rats. J Cell Physiol 2016; 232:447-455. [DOI: 10.1002/jcp.25444] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/26/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Hyung Eun Yim
- Department of Pediatrics; College of Medicine; Korea University; Seoul Korea
| | - Kee Hwan Yoo
- Department of Pediatrics; College of Medicine; Korea University; Seoul Korea
| | - In Sun Bae
- Department of Pediatrics; College of Medicine; Korea University; Seoul Korea
| | - Young Sook Hong
- Department of Pediatrics; College of Medicine; Korea University; Seoul Korea
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20
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Matsushita K, Yang HC, Mysore MM, Zhong J, Shyr Y, Ma LJ, Fogo AB. Effects of combination PPARγ agonist and angiotensin receptor blocker on glomerulosclerosis. J Transl Med 2016; 96:602-9. [PMID: 26999660 PMCID: PMC6117161 DOI: 10.1038/labinvest.2016.42] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 02/10/2016] [Accepted: 02/18/2016] [Indexed: 01/01/2023] Open
Abstract
We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.
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Affiliation(s)
- Keizo Matsushita
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA,These authors contributed equally to this work
| | - Hai-Chun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA,These authors contributed equally to this work
| | - Manu M Mysore
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA,Louisiana State University Health Sciences Center, New Orleans, LA, USA and
| | - Jianyong Zhong
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yu Shyr
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Li-Jun Ma
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury. J Transl Med 2016; 96:547-60. [PMID: 26878135 DOI: 10.1038/labinvest.2016.34] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 12/17/2015] [Accepted: 01/17/2016] [Indexed: 11/09/2022] Open
Abstract
Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.
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22
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Rizzo P, Novelli R, Benigni A, Remuzzi G. Inhibiting angiotensin-converting enzyme promotes renal repair by modulating progenitor cell activation. Pharmacol Res 2016; 108:16-22. [PMID: 27095084 DOI: 10.1016/j.phrs.2016.04.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 04/13/2016] [Indexed: 11/18/2022]
Abstract
Independently of the initial insult, activation and accumulation of parietal progenitor cells within the Bowman's space is a peculiar feature of proliferative chronic kidney diseases. Clinical and experimental studies demonstrated that, in the presence of extensive renal damage, progenitor cells proliferate excessively in the failed attempt to replace the injured podocytes, contributing to the development of crescentic lesions. Inhibiting angiotensin-converting enzyme (ACE) halts crescent formation and promotes the restoration of normal glomerular architecture by limiting progenitor cell proliferation and migration towards the glomerular tuft. Among the mediators involved in the dysregulated response of renal precursors, the angiotensin II (ang II)/ang II type-1 (AT1) receptor/CXCR4 pathway have been demonstrated to be crucial in proliferative diseases. Understanding the mechanisms underlying the formation of crescentic lesions could be instrumental to developing new therapies, which can be more effective and more targeted to molecular mediators than the currently used cytotoxic agents.
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Affiliation(s)
- Paola Rizzo
- IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Rubina Novelli
- IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Ariela Benigni
- IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
| | - Giuseppe Remuzzi
- IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
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23
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Luo WM, Kong J, Gong Y, Liu XQ, Yang RX, Zhao YX. Tongxinluo Protects against Hypertensive Kidney Injury in Spontaneously-Hypertensive Rats by Inhibiting Oxidative Stress and Activating Forkhead Box O1 Signaling. PLoS One 2015; 10:e0145130. [PMID: 26673167 PMCID: PMC4686063 DOI: 10.1371/journal.pone.0145130] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 11/27/2015] [Indexed: 12/18/2022] Open
Abstract
Hypertension is an independent risk factor for the progression of chronic renal failure, and oxidative stress plays a critical role in hypertensive renal damage. Forkbox O1(FoxO1) signaling protects cells against oxidative stress and may be a useful target for treating oxidative stress-induced hypertension. Tongxinluo is a traditional Chinese medicine with cardioprotective and renoprotective functions. Therefore, this study aimed to determine the effects of Tongxinluo in hypertensive renal damage in spontaneously hypertensive rats(SHRs)and elucidate the possible involvement of oxidative stress and FoxO1 signaling in its molecular mechanisms. SHRs treated with Tongxinluo for 12 weeks showed a reduction in systolic blood pressure. In addition to increasing creatinine clearance, Tongxinluo decreased urinary albumin excretion, oxidative stress injury markers including malondialdehyde and protein carbonyls, and expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and its activity in SHR kidneys. While decreasing phosphorylation of FoxO1, Tongxinluo also inhibited the phosphorylation of extracellular signal-regulated kinase1/2 and p38 and enhanced manganese superoxide dismutase and catalase activities in SHR kidneys. Furthermore, histology revealed attenuation of glomerulosclerosis and renal podocyte injury, while Tongxinluo decreased the expression of α-smooth muscle actin, extracellular matrixprotein, transforming growth factor β1 and small mothers against decapentaplegic homolog 3,and improved tubulointerstitial fibrosis in SHR kidneys. Finally, Tongxinluo inhibited inflammatory cell infiltration as well as expression of tumor necrosis factor-α and interleukin-6. In conclusion, Tongxinluo protected SHRs against hypertension-induced renal injury by exerting antioxidant, antifibrotic, and anti-inflammatory activities. Moreover, the underlying mechanisms of these effects may involve inhibition of oxidative stress and functional activation of FoxO1 signaling.
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Affiliation(s)
- Wei-min Luo
- Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, Shandong, China
- Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Jing Kong
- Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yan Gong
- Department of Magnetic Resonance Imaging, Jinan hospital of infectious diseases, Jinan, Shandong, China
| | - Xiao-qiong Liu
- Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Rui-xue Yang
- Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yu-xia Zhao
- Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
- * E-mail:
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24
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Skrypnyk NI, Sanker S, Skvarca LB, Novitskaya T, Woods C, Chiba T, Patel K, Goldberg ND, McDermott L, Vinson PN, Calcutt MW, Huryn DM, Vernetti LA, Vogt A, Hukriede NA, de Caestecker MP. Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury. Am J Physiol Renal Physiol 2015; 310:F705-F716. [PMID: 26661656 DOI: 10.1152/ajprenal.00503.2015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 12/03/2015] [Indexed: 02/07/2023] Open
Abstract
No therapies have been shown to accelerate recovery or prevent fibrosis after acute kidney injury (AKI). In part, this is because most therapeutic candidates have to be given at the time of injury and the diagnosis of AKI is usually made too late for drugs to be efficacious. Strategies to enhance post-AKI repair represent an attractive approach to address this. Using a phenotypic screen in zebrafish, we identified 4-(phenylthio)butanoic acid (PTBA), which promotes proliferation of embryonic kidney progenitor cells (EKPCs), and the PTBA methyl ester UPHD25, which also increases postinjury repair in ischemia-reperfusion and aristolochic acid-induced AKI in mice. In these studies, a new panel of PTBA analogs was evaluated. Initial screening was performed in zebrafish EKPC assays followed by survival assays in a gentamicin-induced AKI larvae zebrafish model. Using this approach, we identified UPHD186, which in contrast to UPHD25, accelerates recovery and reduces fibrosis when administered several days after ischemia-reperfusion AKI and reduces fibrosis after unilateral ureteric obstruction in mice. UPHD25 and 186 are efficiently metabolized to the active analog PTBA in liver and kidney microsome assays, indicating both compounds may act as PTBA prodrugs in vivo. UPHD186 persists longer in the circulation than UPHD25, suggesting that sustained levels of UPHD186 may increase efficacy by acting as a reservoir for renal metabolism to PTBA. These findings validate use of zebrafish EKPC and AKI assays as a drug discovery strategy for molecules that reduce fibrosis in multiple AKI models and can be administered days after initiation of injury.
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Affiliation(s)
- Nataliya I Skrypnyk
- Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee
| | - Subramaniam Sanker
- Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Tatiana Novitskaya
- Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee
| | - Clara Woods
- Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Takuto Chiba
- Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.,Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - Kevin Patel
- Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee
| | - Natasha D Goldberg
- Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Lee McDermott
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Paige N Vinson
- Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
| | - M Wade Calcutt
- Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee
| | - Donna M Huryn
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Lawrence A Vernetti
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Andreas Vogt
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; and
| | - Neil A Hukriede
- Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mark P de Caestecker
- Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee; .,Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
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25
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Xu F, Liu H, Sun Y. Association of plasminogen activator inhibitor-1 gene polymorphism and type 2 diabetic nephropathy. Ren Fail 2015; 38:157-62. [DOI: 10.3109/0886022x.2015.1089464] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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26
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Zakaria E, Al-Din MH, Ghanem NS, Sadik NA, Assem M, Taha F. Urinary albumin excretion and progression of renal disease with impaired fibrinolytic activity in type 2 diabetes mellitus. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2015. [DOI: 10.4103/1110-7782.165450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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27
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Zhou YS, Ihmoda IA, Phelps RG, Bellamy CO, Turner AN. Following specific podocyte injury captopril protects against progressive long term renal damage. F1000Res 2015; 4:172. [PMID: 26629332 PMCID: PMC4642846 DOI: 10.12688/f1000research.4030.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/05/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model. METHODS We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group. RESULTS After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05). CONCLUSIONS Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury.
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Affiliation(s)
- Yu S Zhou
- Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK
| | - Ihmoda A Ihmoda
- Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK
| | - Richard G Phelps
- Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK
| | - Christopher Os Bellamy
- Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK
| | - A Neil Turner
- Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK
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28
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Hishikawa K, Takase O, Yoshikawa M, Tsujimura T, Nangaku M, Takato T. Adult stem-like cells in kidney. World J Stem Cells 2015; 7:490-494. [PMID: 25815133 PMCID: PMC4369505 DOI: 10.4252/wjsc.v7.i2.490] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/31/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration.
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29
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Poosti F, Bansal R, Yazdani S, Prakash J, Post E, Klok P, van den Born J, de Borst MH, van Goor H, Poelstra K, Hillebrands JL. Selective delivery of IFN-γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis. FASEB J 2015; 29:1029-42. [PMID: 25466892 DOI: 10.1096/fj.14-258459] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Renal fibrosis leads to end-stage renal disease demanding renal replacement therapy because no adequate treatment exists. IFN-γ is an antifibrotic cytokine that may attenuate renal fibrosis. Systemically administered IFN-γ causes side effects that may be prevented by specific drug targeting. Interstitial myofibroblasts are the effector cells in renal fibrogenesis. Here, we tested the hypothesis that cell-specific delivery of IFN-γ to platelet-derived growth factor receptor β (PDGFRβ)-expressing myofibroblasts attenuates fibrosis in an obstructive nephropathy [unilateral ureteral obstruction (UUO)] mouse model. PEGylated IFN-γ conjugated to PDGFRβ-recognizing peptide [(PPB)-polyethylene glycol (PEG)-IFN-γ] was tested in vitro and in vivo for antifibrotic properties and compared with free IFN-γ. PDGFRβ expression was >3-fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with α-smooth muscle actin-positive (SMA(+)) myofibroblasts. In vitro, PPB-PEG-IFN-γ significantly inhibited col1a1, col1a2, and α-SMA mRNA expression in TGF-β-activated NIH3T3 fibroblasts (P < 0.05). In vivo, PPB-PEG-IFN-γ specifically accumulated in PDGFRβ-positive myofibroblasts. PPB-PEG-IFN-γ treatment significantly reduced renal collagen I, fibronectin, and α-SMA mRNA and protein expression. Compared with vehicle treatment, PPB-PEG-IFN-γ preserved tubular morphology, reduced interstitial T-cell infiltration, and attenuated lymphangiogenesis (all P < 0.05) without affecting peritubular capillary density. PPB-PEG-IFN-γ reduced IFN-γ-related side effects as manifested by reduced major histocompatibility complex class II expression in brain tissue (P < 0.05 vs. free IFN-γ). Our findings demonstrate that specific targeting of IFN-γ to PDGFRβ-expressing myofibroblasts attenuates renal fibrosis and reduces systemic adverse effects.
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Affiliation(s)
- Fariba Poosti
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Ruchi Bansal
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Saleh Yazdani
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Jai Prakash
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Eduard Post
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Pieter Klok
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Jacob van den Born
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Martin H de Borst
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Harry van Goor
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Klaas Poelstra
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
| | - Jan-Luuk Hillebrands
- *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands
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30
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Abstract
Glomerulosclerosis and interstitial fibrosis increase in the aging kidney, and glomerular filtration rate (GFR) decreases with increasing age. Decreases in stem cell number and function contribute to renal aging. High-dose angiotensin receptor blocker (ARB) not only slows the progression of glomerular and vascular sclerosis in aging but can also induce regression of these processes independently of its hemodynamic actions. By using new interventions, such as peroxisome proliferator activator receptor gamma (PPARγ) agonist, we can manipulate the process of renal aging by regulating stem cells and other mechanisms.
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31
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Yim HE, Yoo KH, Bae IS, Hong YS, Lee JW. Differential modification of enalapril in the kidneys of lean and 'programmed' obese male young rats. Obes Res Clin Pract 2014; 9:281-92. [PMID: 25262233 DOI: 10.1016/j.orcp.2014.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 08/21/2014] [Accepted: 09/02/2014] [Indexed: 01/03/2023]
Abstract
OBJECTIVE We investigated whether enalapril treatment could have beneficial effects on nutritionally-programmed renal changes in postnatally overfed young rats. METHODS Three or 10 male pups per mother were assigned to either the Obese or Lean groups during the first 21 days of life. These pups were treated with enalapril (Obese enalapril, OE; Lean enalapril, LE) or vehicle (Obese control, OC; Lean control, LC) between 15 and 28 days. All pups had their kidneys examined at 29 days. RESULTS OC pups weighed more than those in the LC group between 7 and 28 days of age (P<0.05). Enalapril reduced body weights in rats from both the Obese and Lean groups between 22 and 28 days (P<0.05). Renal cell proliferation and apoptosis, glomerulosclerosis, and tubulointerstitial fibrosis were all increased by enalapril (P<0.05). Among the groups, renal cell apoptosis and serum creatinine were the highest in OE pups (P<0.05). Enalapril treatment resulted in contrasting molecular expression profiles involved in renal maturation and repair in the kidneys of the rats from the Lean and Obese groups. CONCLUSION Enalapril can differentially modulate renal molecular alterations in lean and postnatally overfed rats and may be not beneficial in obese young male rats.
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Affiliation(s)
- Hyung Eun Yim
- Department of Pediatrics, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Kee Hwan Yoo
- Department of Pediatrics, College of Medicine, Korea University, Seoul, Republic of Korea.
| | - In Sun Bae
- Department of Pediatrics, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Young Sook Hong
- Department of Pediatrics, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Joo Won Lee
- Department of Pediatrics, College of Medicine, Korea University, Seoul, Republic of Korea
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32
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Rafiq K, Nishiyama A, Konishi Y, Morikawa T, Kitabayashi C, Kohno M, Masaki T, Mori H, Kobori H, Imanishi M. Regression of glomerular and tubulointerstitial injuries by dietary salt reduction with combination therapy of angiotensin II receptor blocker and calcium channel blocker in Dahl salt-sensitive rats. PLoS One 2014; 9:e107853. [PMID: 25233358 PMCID: PMC4169441 DOI: 10.1371/journal.pone.0107853] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 08/15/2014] [Indexed: 12/24/2022] Open
Abstract
A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.
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Affiliation(s)
- Kazi Rafiq
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- * E-mail:
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yoshio Konishi
- Division of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan
| | - Takashi Morikawa
- Division of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan
| | - Chizuko Kitabayashi
- Division of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan
| | - Masakazu Kohno
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hirohito Mori
- Department of Gastroenterology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hiroyuki Kobori
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Masahito Imanishi
- Division of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan
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33
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Yang HC, Fogo AB. Mechanisms of disease reversal in focal and segmental glomerulosclerosis. Adv Chronic Kidney Dis 2014; 21:442-7. [PMID: 25168834 DOI: 10.1053/j.ackd.2014.04.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 03/25/2014] [Accepted: 04/30/2014] [Indexed: 01/13/2023]
Abstract
It is well known that progression of chronic kidney disease can be ameliorated or stabilized by different interventions, but more studies indicate that it can even be reversed. Most data suggest that current therapy, especially renin-angiotensin system inhibition alone, is not sufficient to initiate and maintain long-term regression of glomerular structural injury. In this article, we review the potential reversal of glomerulosclerosis and evidence from both human and animal studies. We discuss mechanisms that involve matrix remodeling, capillary reorganization, and podocyte reconstitution. In the future, a multipronged strategy including novel anti-inflammatory and antifibrotic molecules should be considered to potentiate regression of glomerulosclerosis.
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Karadeniz T, Cavusoğlu T, Turkmen E, Uyanıkgil Y, Karadeniz M, Akdemir O, Tuglu MI, Ates U, Erbas O. Experimental comparison of protective characteristics of enalapril and trimetazidine in diabetic nephropathy. Ren Fail 2014; 36:1283-1290. [PMID: 25010195 DOI: 10.3109/0886022x.2014.930331] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Abstract Hyperglycemia, hypertension, dyslipidemia, and inflammation have been proposed to account for the development of nephropathy in diabetic subjects. The beneficial effects of enalapril on diabetic nephropathy are known. However, the effects of trimetazidine (TMZ) are still unknown. We aimed at comparing the effects of the enalapril and TMZ treatment on fibronectin expression, inducible nitric oxide synthase expression, urine proteinuria, blood glucose and glomerular, and mesangial structures of kidney in rats that take streptozotocin (STZ). In this study, 32 male Sprague-Dawley albino mature rats of 8 weeks, weighing 200-220 g were used. Diabetes was induced by intraperitoneal injection of STZ (60 mg/kg) for 24 rats. We made four groups (Group 1: control, non-diabetic rats (n = 8), Group 2: diabetes, without treatment (n = 8), Group 3: diabetes treatment with enalapril (n = 8), Group 4: diabetes treatment with TMZ (n = 8). The positive effects of renal tissue and tubules in the mesangium immunohistochemical were shown in TMZ receiving rat groups. These positive effects were in parallel with the reduction in fibronectin and I-NOS expression and reduction in the proteinuria. TMZ and enalapril treatment of diabetic rats and renal parenchyma in this study are shown to have positive effects on the different levels.
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Affiliation(s)
- Tugba Karadeniz
- Department of Pathology, Izmir Tepecik Training and Research Hospital , Izmir , Turkey
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Griffin KA, Polichnowski A, Litbarg N, Picken M, Venkatachalam MA, Bidani AK. Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model. Hypertension 2014; 64:801-7. [PMID: 24958497 DOI: 10.1161/hypertensionaha.114.03609] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest blood pressure (BP) reductions to below this threshold regardless of antihypertensive class (1) should prevent MN and (2) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke-prone spontaneously hypertensive rats receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mm Hg) and MN (histological damage score 36±5; n=27) developed in the untreated stroke-prone spontaneously hypertensive rats but were prevented by all antihypertensive classes (enalapril [n=15], amlodipine [n=13], or a hydralazine/hydrochlorothiazide combination [n=15]) if the final 2-week systolic BP remained <190 mm Hg. More impressively, modest systolic BP reductions to 160 to 180 mm Hg (hydralazine/hydrochlorothiazide regimen) initiated at ≈4 weeks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2 to 3 weeks (post-therapy left kidney injury score 9±2, P<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hours before therapy to 20.5±3.6 mg 1 week later. These data clearly demonstrate the barotrauma-mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.
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Affiliation(s)
- Karen A Griffin
- From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.).
| | - Aaron Polichnowski
- From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.)
| | - Natalia Litbarg
- From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.)
| | - Maria Picken
- From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.)
| | - Manjeri A Venkatachalam
- From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.)
| | - Anil K Bidani
- From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.)
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Abstract
BACKGROUND Several organs such as the skin and liver have a great capacity for regeneration. However, many approaches only delay the progression of end-stage kidney disease and do not achieve efficient long-term stabilization, let alone regeneration. SUMMARY In mammals, the kidney has an innate but limited capacity for regeneration which can only modify the nephron structure and function but not increase the nephron number. Several clinical and animal studies have indicated that functional improvements and/or structural regression can occur in chronic kidney disease. Cell reconstitution, matrix remodeling, and tissue reorganization are major mechanisms for kidney regeneration. Current approaches achieve only partial kidney regeneration, but this does not occur in all animals and is not sustained in the long term. Multipronged and early interventions are future choices for the induction of kidney regeneration. KEY MESSAGES Kidney regeneration in mammals is feasible but limited and may be enhanced by multitargeting key mechanisms.
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Affiliation(s)
- Hai-Chun Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tenn., USA
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Abstract
Aging is associated with structural and functional changes in the kidney. Structural changes include glomerulosclerosis, thickening of the basement membrane, increase in mesangial matrix, tubulointerstitial fibrosis and arteriosclerosis. Glomerular filtration rate is maintained until the fourth decade of life, after which it declines. Parallel reductions in renal blood flow occur with redistribution of blood flow from the cortex to the medulla. Other functional changes include an increase in glomerular basement permeability and decreased ability to dilute or concentrate urine.
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Affiliation(s)
- Zeina Karam
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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38
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Postnatal early overnutrition causes long-term renal decline in aging male rats. Pediatr Res 2014; 75:259-65. [PMID: 24232634 DOI: 10.1038/pr.2013.223] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 07/04/2013] [Indexed: 01/05/2023]
Abstract
BACKGROUND We evaluated the influence of postnatal early overnutrition on renal pathophysiological changes in aging rats. METHODS Three or 10 male pups per mother were assigned to either the small litter (SL) or normal litter (control) groups, respectively, during the first 21 d of life. The effects of early postnatal overnutrition were determined at 12 mo. RESULTS SL rats weighed more than controls between 4 d and 6 mo of age (P < 0.05). However, between 6 and 12 mo, body weights in both groups were not different. In the SL group, at 12 mo, systolic blood pressure was higher and creatinine clearance was lower than the same in controls (P < 0.05). Numbers of CD68 (ED1)-positive macrophages and apoptotic cells in renal cortex were higher in SL rats (P < 0.05). Furthermore, index scores for glomerulosclerosis and tubulointerstitial fibrosis were higher in the SL group (P < 0.05). Significantly less glomeruli per section area were found in aging SL rats (P < 0.05). Immunoblotting and immunohistochemistry showed decreased intrarenal renin expression in SL rats (P < 0.05). CONCLUSION Early postnatal overnutrition can potentiate structural and functional abnormalities in the aging kidney and can lead to systolic hypertension with reduced intrarenal renin activity.
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Lim BJ, Yang HC, Fogo AB. Animal models of regression/progression of kidney disease. ACTA ACUST UNITED AC 2014; 11:45-51. [PMID: 25722733 DOI: 10.1016/j.ddmod.2014.06.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Current medical therapies may delay chronic kidney disease progression. However, increasing experimental evidence indicates remission or even regression can be achieved. In order to study mechanisms progression vs. regression by different interventions, appropriate animal models and research design must be implemented. We review key information of selected models, including etiology, pathogenesis, procedure, time course and assessment of potential regression.
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Affiliation(s)
- Beom Jin Lim
- Dept. of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States ; Dept. of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Hai-Chun Yang
- Dept. of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Agnes B Fogo
- Dept. of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
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40
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Atkinson JM, Pullen N, Johnson TS. An inhibitor of thrombin activated fibrinolysis inhibitor (TAFI) can reduce extracellular matrix accumulation in an in vitro model of glucose induced ECM expansion. Matrix Biol 2013; 32:277-87. [PMID: 23369837 DOI: 10.1016/j.matbio.2013.01.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 01/18/2013] [Accepted: 01/18/2013] [Indexed: 12/29/2022]
Abstract
Chronic kidney disease (CKD) is characterised by the pathological accumulation of extracellular matrix (ECM) proteins leading to progressive kidney scarring via glomerular and tubular basement membrane expansion. Increased ECM synthesis and deposition, coupled with reduced ECM breakdown contribute to the elevated ECM level in CKD. Previous pre-clinical studies have demonstrated that increased plasmin activity has a beneficial effect in the protein overload model of CKD. As plasmin activation is downregulated by the action of the thrombin activated fibrinolytic inhibitor (TAFI), we tested the hypothesis that inhibition of TAFI might increase plasmin activity and reduce ECM accumulation in an in vitro model of glucose induced ECM expansion. Treatment of NRK52E tubular epithelial cells with increasing concentrations of glucose resulted in a 40% increase in TAFI activity, a 38% reduction in plasmin activity and a subsequent increase in ECM accumulation. In this model system, application of the previously reported TAFI inhibitor UK-396082 [(2S)-5-amino-2-[(1-n-propyl-1H-imidazol-4-yl)methyl]pentanoic acid] caused a reduction in TAFI activity, increased plasmin activity and induced a parallel decrease in ECM levels. In contrast, RNAi knockdown of plasmin resulted in an increase in ECM levels. The data presented here indicate that high glucose induces TAFI activity, inhibiting plasmin activation which results in elevated ECM levels in tubular epithelial cells. The results support the hypothesis that UK-396082 is able to reduce TAFI activity, normalising plasmin activity and preventing excess ECM accumulation suggesting that TAFI inhibition may have potential as an anti-scarring strategy in CKD.
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MESH Headings
- Amino Acids/pharmacology
- Animals
- Carboxypeptidase B2/antagonists & inhibitors
- Carboxypeptidase B2/genetics
- Carboxypeptidase B2/metabolism
- Cell Line
- Enzyme Inhibitors/pharmacology
- Epithelial Cells/drug effects
- Epithelial Cells/enzymology
- Epithelial Cells/pathology
- Extracellular Matrix/drug effects
- Extracellular Matrix/enzymology
- Extracellular Matrix/pathology
- Fibrinolysin/antagonists & inhibitors
- Fibrinolysin/genetics
- Fibrinolysin/metabolism
- Fibrinolysis/drug effects
- Fibrinolysis/genetics
- Gene Expression/drug effects
- Glucose/adverse effects
- Humans
- Imidazoles/pharmacology
- Kidney Tubules, Proximal/drug effects
- Kidney Tubules, Proximal/enzymology
- Kidney Tubules, Proximal/pathology
- Models, Biological
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Rats
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/enzymology
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/pathology
- Thrombin/genetics
- Thrombin/metabolism
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Affiliation(s)
- J M Atkinson
- Sheffield Kidney Institute & Academic Unit of Nephrology, University of Sheffield, S10 2RX, United Kingdom
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Romagnani P, Lasagni L, Remuzzi G. Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Nat Rev Nephrol 2013; 9:137-46. [PMID: 23338209 DOI: 10.1038/nrneph.2012.290] [Citation(s) in RCA: 151] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Following kidney injury, repair can result in functional tissue becoming a patch of cells and disorganized extracellular matrix--a scar--or it can recapitulate the original tissue architecture through the process of regeneration. Regeneration can potentially occur in all animal species and humans. Indeed, the repair of portions of the existing nephron after tubular damage, a response that has been designated classically as cellular regeneration, is conserved in all animal species from the ancestral phases of evolution. By contrast, another type of regenerative response--nephron neogenesis--has been described in lower branches of the animal kingdom, but does not occur in adult mammals. Converging evidence suggests that a renal progenitor system is present in the adult kidney across different stages of evolution, with renal progenitors having been identified as the main drivers of kidney regenerative responses in fish, insects, rodents and humans. In this Review, we describe similarities and differences between the renal progenitor systems through evolution, and propose explanations for how progressive kidney adaptation to environmental changes both required and permitted neonephrogenesis to be given up and for cellular regeneration to be retained as the main regenerative strategy. Understanding the mechanisms that drive renal progenitor growth and differentiation represent the key step for modulating this potential for therapeutic purposes.
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Affiliation(s)
- Paola Romagnani
- Pediatric Nephrology Unit, Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, 50139 Florence, Italy.
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Yim HE, Ha KS, Bae IS, Yoo KH, Hong YS, Lee JW. Overweight, hypertension and renal dysfunction in adulthood of neonatally overfed rats. J Nutr Biochem 2013; 24:1324-33. [PMID: 23333086 DOI: 10.1016/j.jnutbio.2012.10.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 10/16/2012] [Accepted: 10/16/2012] [Indexed: 12/26/2022]
Abstract
Accelerated growth in early infancy has been associated with later cardiovascular and metabolic diseases. We investigated the influence of overnutrition during neonatal periods on the development of renal pathophysiological changes in adult offspring rats. Three or 10 male pups per mother were assigned to either the small litter (SL) or normal litter (NL) control groups during the first 21 days of life. The effects of early postnatal overnutrition on body weight, blood pressure and renal changes were determined at 3 and 6 months. Pups in the SL group weighed more than controls between 7 days and 6 months of age (P<.05). In the SL group, serum creatinine levels were higher at 3 and 6 months (P<.05), and at 6 months, blood pressure levels were higher than those of the controls (P<.05). The number of ED-1 positive macrophages in renal cortex and glomerulosclerosis index increased in the SL group at 3 and 6 months (P<.05). Additionally, cortical apoptotic cells increased in the SL group at 6 months (P<.05). Immunoblotting and immunohistochemistry showed that matrix metalloproteinase (MMP)-9 protein expressions decreased and tissue inhibitor of MMP-1, tumor necrosis factor-α, osteopontin and adiponectin expressions increased in the SL group at 3 months (P<.05). However, at 6 months, MMP-9 expression was elevated, and osteopontin expression remained elevated in the SL group (P<.05). Early postnatal overfeeding can lead to lasting overweight, hypertension and renal dysfunction and place a greater burden on the kidney.
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Affiliation(s)
- Hyung Eun Yim
- Department of Pediatrics, College of Medicine, Korea University, Seoul 152-703, South Korea
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Romagnani P, Remuzzi G. Renal progenitors in non-diabetic and diabetic nephropathies. Trends Endocrinol Metab 2013; 24:13-20. [PMID: 23046584 DOI: 10.1016/j.tem.2012.09.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 08/26/2012] [Accepted: 09/05/2012] [Indexed: 11/18/2022]
Abstract
Chronic kidney disease represents a major health problem worldwide. Although the kidney has the ability to repopulate structures that have sustained some degree of injury, the mechanisms underlying its regenerative capacity have been unclear. Recent evidence now supports the existence of a renal progenitor system able to replace podocytes and tubular cells, localized within the urinary pole of Bowman's capsule and along the tubule. Altered growth or differentiation of renal progenitors has been reported in several renal disorders including diabetic nephropathy. Pharmacological modulation of renal progenitor growth or differentiation can enhance kidney regeneration, suggesting that treatments aimed at reversing kidney injury are possible. Renal progenitors may represent a novel target in diabetic nephropathy and other kidney disorders.
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Affiliation(s)
- Paola Romagnani
- Center of Excellence for Molecular and Clinical Studies on Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Florence, Italy.
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Potthoff SA, Sitek B, Stegbauer J, Schulenborg T, Marcus K, Quack I, Rump LC, Meyer HE, Stühler K, Vonend O. The glomerular proteome in a model of chronic kidney disease. Proteomics Clin Appl 2012; 2:1127-39. [PMID: 21136910 DOI: 10.1002/prca.200800010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Adequate kidney function is crucial in sustaining vertebrate homeostasis. Certain diseases can diminish renal function and lead to end-stage renal disease. Diabetes mellitus and hypertension are the main causes of glomerulosclerosis and albuminuria in adults. The molecular mechanisms that trigger these maladaptive changes are still unsatisfyingly described. We previously introduced 2-D DIGE in combination with focused tissue isolation methods to analyze protein expression in glomeruli. Glomeruli, the crucial compartments in albuminuric renal diseases, were extracted using magnetic particles from subtotally nephrectomized FVB mice (n = 6); this 5/6 nephrectomy in FVB mice is a model of chronic kidney disease. Analysis of protein expression levels from glomerular protein lysates was performed using 2-D DIGE and compared with glomerular protein lysates from mice that underwent sham surgery. The comparison of about 2100 detectable spots between both groups revealed 48 protein spots that showed significant differential expression. Of those, 33 proteins could be identified using nanoLC-ESI MS. The metalloproteinase meprin 1 alpha, the beta galactoside-binding-lectin galectin-1 and dimethylarginine dimethylaminohydrolase 1, a key enzyme in NO metabolism, were found to be differentially regulated, thus implying a role in the pathogenesis and pathophysiology of progressive kidney disease. In conclusion, 2-D DIGE protein analysis of smallest sample sizes from specific organ compartments provides focused protein expression results, which help in gaining an understanding of the molecular mechanisms of chronic kidney disease.
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Affiliation(s)
- Sebastian A Potthoff
- Marienhospital Herne, Klinikum der Ruhr-Universität Bochum, Bochum, Germany; Department of Pathology, Vanderbilt University, Nashville, USA
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Prunotto M, Budd DC, Gabbiani G, Meier M, Formentini I, Hartmann G, Pomposiello S, Moll S. Epithelial-mesenchymal crosstalk alteration in kidney fibrosis. J Pathol 2012; 228:131-47. [PMID: 22570261 DOI: 10.1002/path.4049] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 04/19/2012] [Accepted: 04/26/2012] [Indexed: 02/06/2023]
Abstract
The incidence of chronic kidney diseases (CKD) is constantly rising, reaching epidemic proportions in the western world and leading to an enormous threat, even to modern health-care systems, in industrialized countries. Therapies of CKD have greatly improved following the introduction of drugs targeting the renin-angiotensin system (RAAS) but even this refined pharmacological approach has failed to stop progression to end-stage renal disease (ESRD) in many individuals. In vitro historical data and recent new findings have suggested that progression of renal fibrosis might occur as a result of an altered tubulo-interstitial microenvironment and, more specifically, as a result of an altered epithelial-mesenchymal crosstalk. Here we the review biological findings that support the hypothesis of an altered cellular crosstalk in an injured local tubulo-interstitial microenvironment leading to renal disease progression. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Marco Prunotto
- CV and Metabolic DTA Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
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Yuan J, Wang X, Chen T, Chen G, Lu Y. Salvia miltiorrhiza Depresses Plasminogen Activator Inhibitor-1 Production Through Inhibition of Angiotensin II. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2012; 36:1005-15. [PMID: 19051364 DOI: 10.1142/s0192415x08006405] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The purpose of this study was to investigate the effect of Salvia miltiorrhiza on the production of plasminogen activator inhibitor-1(PAI-1) induced by angiotensin II (Ang II) in renal mesangial cells. Rat mesangial cells were exposed to 100 nM Ang II. Meanwhile, different concentrations of Salvia miltiorrhiza injection were added to Mesangial Cells. PAI-1 mRNA was measured by semi-quantification reverse transcriptase polymerase chain reaction (RT-PCR) and PAI-1 protein by Western blotting. ELISA was used to detect the expression of transforming growth factor β1(TGF-β1) in serum free MEM medium. The level of cellular reactive oxygen species (ROS) was measured by confocal laser scanning microscopy. Salvia miltiorrhiza notably attenuated expression of PAI-1 induced by Ang II in a concentration-dependent manner. Meanwhile, it suppressed the production of TGF-β1and cellular ROS in mesangial cells. These effects were due to Salvia miltiorrhiza's ability of inhibiting the activities of angiotensin II. Therefore, Salvia miltiorrhiza can be used to retard progression of glomerular sclerosis.
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Affiliation(s)
- Jun Yuan
- Department of Nephrology, Affiliated Hospital of Hubei Traditional Chinese Medical College, Wuchang 430061, Wuhan City, China
| | - Xiaoqin Wang
- Department of Nephrology, Affiliated Hospital of Hubei Traditional Chinese Medical College, Wuchang 430061, Wuhan City, China
| | - Taohou Chen
- Hubei College of Traditional Chinese Medicine, Special No. 1 Tanhualin, Wuchang 430061, Wuhan City, China
| | - Gang Chen
- Hubei College of Traditional Chinese Medicine, Special No. 1 Tanhualin, Wuchang 430061, Wuhan City, China
| | - Yanfang Lu
- Hubei College of Traditional Chinese Medicine, Special No. 1 Tanhualin, Wuchang 430061, Wuhan City, China
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Ahn JH, Hong HC, Cho MJ, Kim YJ, Choi HY, Eun CR, Yang SJ, Yoo HJ, Kim HY, Seo JA, Kim SG, Choi KM, Baik SH, Choi DS, Kim NH. Effect of eplerenone, a selective aldosterone blocker, on the development of diabetic nephropathy in type 2 diabetic rats. Diabetes Metab J 2012; 36:128-35. [PMID: 22540049 PMCID: PMC3335894 DOI: 10.4093/dmj.2012.36.2.128] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 10/10/2011] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats. METHODS ANIMALS WERE DIVIDED INTO SIX GROUPS AS FOLLOWS: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks. RESULTS Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-β1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups. CONCLUSION Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.
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Affiliation(s)
- Jae Hee Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ho Cheol Hong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Myong Jin Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yoon Jung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hae Yoon Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chai Ryoung Eun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sae Jeong Yang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hye Jin Yoo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hee Young Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ji A Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sin Gon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sei Hyun Baik
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Dong Seop Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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Kim DK, Nam BY, Li JJ, Park JT, Lee SH, Kim DH, Kim JY, Kang HY, Han SH, Yoo TH, Han DS, Kang SW. Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes. Diabetologia 2012; 55:1205-17. [PMID: 22311416 DOI: 10.1007/s00125-012-2467-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS Translationally controlled tumour protein (TCTP) is thought to be involved in cell growth by regulating mTOR complex 1 (mTORC1) signalling. As diabetes characteristically induces podocyte hypertrophy and mTORC1 has been implicated in this process, TCTP may have a role in the pathogenesis of diabetes-induced podocyte hypertrophy. METHODS We investigated the effects and molecular mechanisms of TCTP in diabetic mice and in high glucose-stimulated cultured podocytes. To characterise the role of TCTP, we conducted lentivirus-mediated gene silencing of TCTP both in vivo and in vitro. RESULTS Glomerular production of TCTP was significantly higher in streptozotocin induced-diabetic DBA/2J mice than in control animals. Double-immunofluorescence staining for TCTP and synaptopodin revealed that podocyte was the principal cell responsible for this increase. TCTP knockdown attenuated the activation of mTORC1 downstream effectors and the overproduction of cyclin-dependent kinase inhibitors (CKIs) in diabetic glomeruli, along with a reduction in proteinuria and a decrease in the sizes of podocytes as well as glomeruli. In addition, knockdown of TCTP in db/db mice prevented the development of diabetic nephropathy, as indicated by the amelioration of proteinuria, mesangial expansion, podocytopenia and glomerulosclerosis. In accordance with the in vivo data, TCTP inhibition abrogated high glucose-induced hypertrophy in cultured podocytes, which was accompanied by the downregulation of mTORC1 effectors and CKIs. CONCLUSIONS/INTERPRETATION These findings suggest that TCTP might play an important role in the process of podocyte hypertrophy under diabetic conditions via the regulation of mTORC1 activity and the induction of cell-cycle arrest.
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Affiliation(s)
- D K Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
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Barisoni L. Podocyte biology in segmental sclerosis and progressive glomerular injury. Adv Chronic Kidney Dis 2012; 19:76-83. [PMID: 22449344 DOI: 10.1053/j.ackd.2012.02.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Revised: 02/24/2012] [Accepted: 02/24/2012] [Indexed: 11/11/2022]
Abstract
During the past 2 decades, progress has been made in understanding the biology and mechanisms of podocyte injury and the relationship of these processes to glomerulosclerosis. In addition, studies of human biopsies and animal models have provided insights into the mechanisms of glomerular disease progression and repair. These new developments are critical for establishing better therapeutic guidelines that target specific pathways, which otherwise would lead to irreversible injury.
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Abstract
In the past decade, research has advanced our understanding how endothelin contributes to proteinuria and glomerulosclerosis. Data from pre-clinical and clinical studies now provide evidence that proteinuric diseases such as focal segmental glomerulosclerosis and diabetic nephropathy as well as hypertension nephropathy are sensitive to treatment with endothelin receptor antagonists (ERAs). Like blockade of the renin-angiotensin system, ERA treatment-under certain conditions-may even cause disease regression, effects that could be achieved on top of renin-angiotensin-aldosterone system blockade, suggesting independent therapeutic mechanisms by which ERAs convey nephroprotection. Beneficial effects of ERAs on podocyte function, which is essential to maintain the glomerular filtration barrier, have been identified as one of the key mechanisms by which inhibition of the endothelin ETA receptor ameliorates renal structure and function. In this article, we will review pre-clinical studies demonstrating a causal role for endothelin in proteinuric chronic kidney disease (with a particular focus on functional and structural integrity of podocytes in vitro and in vivo). We will also review the evidence suggesting a therapeutic benefit of ERA treatment on the functional integrity of podocytes in humans.
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Affiliation(s)
- Matthias Barton
- Molecular Internal Medicine, University of Zürich, Zürich, Switzerland
| | - Pierre-Louis Tharaux
- INSERM and Université Paris Descartes, Sorbonne Paris Cité, Paris Cardiovascular Centre, Paris, France
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