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Uzun O, Heybeli C, Kutlu FSA, Celebioglu Pekiner M, Yıldırım F, Cavdar C, Sarioglu S. Relationship between complement and macrophage markers with kidney survival in patients with diabetic nephropathy. Acta Diabetol 2025:10.1007/s00592-025-02521-3. [PMID: 40338344 DOI: 10.1007/s00592-025-02521-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 04/21/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease (ESKD) worldwide. Macrophages and the complement system have interrelated roles in DN. We aimed to determine associations between macrophage and complement markers with the progression of DN. METHODS This retrospective cohort study included patients diagnosed with sole DN by kidney biopsy. Using immunohistochemistry, CD68+ and CD163+ cells and complement markers were counted in glomerular and tubulointerstitial areas. The primary outcome was evolution to ESKD and/or doubling serum creatinine (SCr). RESULTS Forty-six patients were included. The median SCr at baseline was 2.7 (1.41-3.1) mg/dL. During the median follow-up of 32 months (range 6-54), 50% of patients reached the primary outcome. Most of the clinical and histological findings were comparable between progressors and non-progressors, while progressors had a higher median number of glomerular CD68+ cells and a higher percentage of glomerulosclerosis. After adjustments for age, sex, and SCr, the median glomerular CD68+ cell number was the sole independent predictor of progression. Glomerular C4d was associated with nephrotic-range proteinuria but not with the progression of kidney failure. CONCLUSIONS Glomerular CD68+ cell count may serve as a promising predictor of kidney disease progression among patients with DN. Glomerular C4d was associated with nephrotic-range proteinuria but not with the progression of kidney failure.
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Affiliation(s)
- Ozcan Uzun
- Yalova Research and Training Hospital, Yalova, Turkey
| | - Cihan Heybeli
- Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey.
| | | | | | | | - Caner Cavdar
- Division of Nephrology, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Sulen Sarioglu
- Department of Pathology, Dokuz Eylül University School of Medicine, Izmir, Turkey
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Yu S, Han Z, Li C, Lu X, Li Y, Yuan X, Guo D. Cross Talk Between Macrophages and Podocytes in Diabetic Nephropathy: Potential Mechanisms and Novel Therapeutics. Mediators Inflamm 2025; 2025:8140479. [PMID: 40352596 PMCID: PMC12064321 DOI: 10.1155/mi/8140479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 09/11/2024] [Accepted: 04/12/2025] [Indexed: 05/14/2025] Open
Abstract
Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal failure worldwide. Podocytes, essential components of the glomerular filtration barrier (GFB), are profoundly affected in the diabetic milieu, resulting in structural and functional alterations. Concurrently, macrophages, pivotal innate immune cells, infiltrate the diabetic kidney and exhibit diverse activation states influenced by the local environment, playing a crucial role in kidney physiology and pathology. This review synthesizes current insights into how the dynamic cross talk between these two cell types contributes to the progression of DN, exploring the molecular and cellular mechanisms underlying this interaction, with a particular focus on how macrophages influence podocyte survival through various forms of cell death, including apoptosis, pyroptosis, and autophagy. The review also discusses the potential of targeting macrophages to develop more effective treatments for DN.
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Affiliation(s)
- Siming Yu
- Department of Nephrology II, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150036, China
| | - Zehui Han
- First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| | - Chunsheng Li
- First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| | - Xinxin Lu
- First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| | - Yue Li
- First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| | - Xingxing Yuan
- First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150006, China
| | - Dandan Guo
- Department of Cardiology, Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150001, China
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Zhang J, Cheng L, Jiang S, Zhu D. Machine learning based identification of anoikis related gene classification patterns and immunoinfiltration characteristics in diabetic nephropathy. Sci Rep 2025; 15:15271. [PMID: 40312440 PMCID: PMC12046048 DOI: 10.1038/s41598-025-99395-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 04/21/2025] [Indexed: 05/03/2025] Open
Abstract
Anoikis and immune cell infiltration are pivotal factors in the pathophysiological mechanism of diabetic nephropathy (DN), yet a comprehensive understanding of the mechanism is lacking. This work aimed to pinpoint distinctive anoikis-related genes (ARGs) in DN and delve into their impact on the immune landscape. Three datasets (GSE30528, GSE47184, and GSE96804) were downloaded from the gene expression omnibus (GEO) dataset. Differentially expressed genes (DEGs) were identified using the "limma" package, while ARGs were obtained from GSEA, GeneCard, and Harmonizome datasets. The intersection of DEGs and ARGs was analyzed for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The CIBERSORT algorithm was employed to estimate the infiltration percentage of 22 immune cell types in DN renal tissue. Subsequently, the least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) algorithms were adopted to screen key ARGs related to DN. After that, receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of each gene and the real-time quantitative polymerase chain reaction (RT-qPCR) was adopted to quantitatively detect the expression of biomarkers in DN cell models. Finally, correlations between key genes and immune cell infiltration were analyzed, and a competitive endogenous ribonucleic acid (RNA) (ceRNA) network based on key genes was constructed. A total of 59 DEARGs were identified. GO functional annotation enrichment analysis revealed their involvement in kidney development, extracellular matrix (ECM), cytoplasmic vesicle cavity, immunoinflammatory response, and cytokine effect. KEGG pathway analysis indicated that MAPK, PI3K -Akt, IL -17, TNF, and HIF- 1 signaling pathways are critical for DN. In addition, seven key genes, including PDK4, S100A8, HTRA1, CHI3L1, WT1, CDKN1B, and EGF, were screened by machine learning algorithm. Most of these genes exhibited low expression in renal tissue of DN patients and positive correlation with neutrophils, and their expressions were verified in an external dataset cell model. The ceRNA analysis suggested potential regulatory pathways (H19/miR-15b-5p/PDK4 and KCNQ1T1/miR-1207-3p/WT1) influencing early DN progression. This work provided a comprehensive analysis of the role of DEARGs in DN for the first time, offering valuable insights for further understanding the disease mechanism and guiding clinical diagnosis, treatment, and research of DN.
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Affiliation(s)
- Jing Zhang
- The Third Department of Jiaozhou City Traditional Chinese Medicine Hospital, Jiaozhou, 266300, Shandong, China
| | - Lulu Cheng
- Guangzhou University of Chinese Medicine, Guangzhou, 510000, Guangdong, China
| | - Shan Jiang
- Traditional Chinese Medicine Department of Linyi People's Hospital, Linyi, 276000, Shandong, China
| | - Duosheng Zhu
- The Third Department of Jiaozhou City Traditional Chinese Medicine Hospital, Jiaozhou, 266300, Shandong, China.
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4
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Chen W, Wang Y, Xie W, Wang J, Ji X, Feng C, Zhang X. Static magnetic fields alleviate diabetic nephropathy by reducing renal cell inflammation and promoting M2 macrophage polarization. FASEB J 2025; 39:e70424. [PMID: 40013926 DOI: 10.1096/fj.202500061r] [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: 01/08/2025] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 02/28/2025]
Abstract
Diabetic nephropathy (DN) is one of the most severe diabetic complications, which can easily progress into irreversible and detrimental end-stage renal disease if not properly controlled. However, the effective prevention of DN progression has always remained a huge challenge. Moderate intensity static magnetic fields (SMFs), which have the advantages of non-invasive and high penetration, have shown beneficial effects in reducing blood glucose in type 2 diabetes mice in recent years. In this study, by using both db/db severe diabetic mice and high-fat diet and streptozotocin-induced moderate diabetic mice, we found that SMFs have significant effects on reducing DN compared to blood glucose control. Further analyzing the db/db mice with severe diabetes, we found that kidney inflammation, vascular abnormalities, and fibrosis were all greatly reduced. Moreover, SMFs can promote macrophages polarized into M2. In vitro cellular experiments also demonstrate the positive effects of SMFs in reducing kidney cell inflammation, as well as increasing M2 macrophage polarization by promoting F-actin assembly. Therefore, our results show that moderate intensity SMFs have great potential to be developed as a new physical modality to be used in the treatment of DN, and possibly other types of chronic kidney diseases.
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Affiliation(s)
- Weili Chen
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, China
- High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Ying Wang
- High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- Science Island Branch of Graduate School, University of Science and Technology of China, Hefei, China
| | - Wenjing Xie
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, China
- High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Junjun Wang
- High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Xinmiao Ji
- High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- Science Island Branch of Graduate School, University of Science and Technology of China, Hefei, China
| | - Chuanlin Feng
- High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- Science Island Branch of Graduate School, University of Science and Technology of China, Hefei, China
| | - Xin Zhang
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, China
- High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- Science Island Branch of Graduate School, University of Science and Technology of China, Hefei, China
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Zhang RM, Oh J, Wice BM, Dusso A, Bernal-Mizrachi C. Acute hyperglycemia induces podocyte apoptosis by monocyte TNF-α release, a process attenuated by vitamin D and GLP-1 receptor agonists. J Steroid Biochem Mol Biol 2025; 247:106676. [PMID: 39818342 PMCID: PMC11859504 DOI: 10.1016/j.jsbmb.2025.106676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/30/2024] [Accepted: 01/13/2025] [Indexed: 01/18/2025]
Abstract
Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-α secretion causing podocyte apoptosis. The AH-induced monocyte TNF-α secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-α release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-α secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-α release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel anti-inflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes.
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Affiliation(s)
- Rong M Zhang
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jisu Oh
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
| | - Burton M Wice
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
| | - Adriana Dusso
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
| | - Carlos Bernal-Mizrachi
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, VA Medical Center, St. Louis, MO, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
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Xu J, Zhao Y, Tyler Mertens R, Ding Y, Xiao P. Sweet regulation - The emerging immunoregulatory roles of hexoses. J Adv Res 2025; 69:361-379. [PMID: 38631430 PMCID: PMC11954837 DOI: 10.1016/j.jare.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 03/20/2024] [Accepted: 04/13/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells. AIM OF REVIEW Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field. KEY SCIENTIFIC CONCEPTS OF REVIEW Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.
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Affiliation(s)
- Junjie Xu
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuening Zhao
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | | | - Yimin Ding
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.
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7
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Li R, Yan X, Zhao Y, Liu H, Wang J, Yuan Y, Li Q, Su J. Oxidative Stress Induced by Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) Dysfunction Aggravates Chronic Inflammation Through the NAD +/SIRT3 Axis and Promotes Renal Injury in Diabetes. Antioxidants (Basel) 2025; 14:267. [PMID: 40227196 PMCID: PMC11939224 DOI: 10.3390/antiox14030267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 04/15/2025] Open
Abstract
Diabetic nephropathy (DN), one of the most common and severe microvascular complications of diabetes, significantly increases the risk of renal failure and cardiovascular events. A high-glucose environment can lead to mitochondrial dysfunction in macrophages, which, through remodeling of energy metabolism, mediates the polarization of a pro-inflammatory phenotype and contributes to the formation of a chronic inflammatory microenvironment. Recent studies have found that high-glucose stimulation induces dysregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) redox pathway in macrophages, leading to the generation of oxidative stress (OS) that further drives chronic inflammation. Therefore, it is crucial to fully understand how OS affects macrophage phenotypes and functions following NRF2 inhibition. This review analyzes the role of OS induced by NRF2 dysfunction in the chronic inflammation of DN and explores the relationship between OS and macrophage mitochondrial energy metabolism through the NAD⁺/NADH-SIRT3 axis, providing new therapeutic targets for targeting OS to improve the inflammatory microenvironment and vascular damage in DN.
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Affiliation(s)
| | | | | | | | | | | | | | - Jing Su
- Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, College of Basical Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130012, China
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Zhang B, Wu Y, Wang Z, Gao S, Liu H, Lin Y, Yu P. Unveiling macrophage dynamics and efferocytosis-related targets in diabetic kidney disease: insights from single-cell and bulk RNA-sequencing. Front Immunol 2025; 16:1521554. [PMID: 40046045 PMCID: PMC11879818 DOI: 10.3389/fimmu.2025.1521554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 01/28/2025] [Indexed: 05/13/2025] Open
Abstract
Background Chronic inflammation and immune imbalance mediated by macrophages are considered pivotal in diabetic kidney disease (DKD). The study aims to clarify the macrophage heterogeneity and phenotype dynamics, and pinpoint critical targets within efferocytosis in DKD. Methods Utilizing early human DKD sequencing data, we computed the potential communication between leukocytes and renal intrinsic cells. Subsequently, we scrutinized the single-cell RNA sequencing (scRNA-seq) data from CD45-enriched immune cells, concentrating on the macrophage subsets in DKD. Pseudotime trajectory analysis was conducted to explore cell development. Differential expression genes (DEGs) from macrophage subgroups and bulk RNA-sequencing were used to identify shared hub genes. The NephroseqV5 platform was employed to evaluate the clinical significance, and the expression of key molecules was validated in DKD tissues. Results Macrophage infiltration rose in DKD, causing inflammation through the release of chemokines. As time progressed, the number of resident macrophages substantially dropped, with diminishing M1-like and increasing M2-like phenotypes relative to early stages. Further analysis pointed to the most enrichment of macrophage function is the phagosome. We overlapped the DEGs with efferocytosis-related genes and identified key genes, including CD36, ITGAM, and CX3CR1, which exhibited significant correlations with macrophages and T cells. The Nephroseq database revealed that they are associated with proteinuria and renal function. Consistent with the validation set, in vivo experiments verified elevated expression levels of key molecules. Conclusions In essence, our research elucidated the dynamics in macrophage subtype transitions. It emphasized three pivotal genes as critical modulators of macrophage efferocytosis in DKD, indicating their potential as innovative biomarkers and therapeutic targets.
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Affiliation(s)
- Binshan Zhang
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Yunqi Wu
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Zhongli Wang
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Suhua Gao
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Hongyan Liu
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Yao Lin
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Pei Yu
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
- Department of Nephrology & Blood Purification Center, The Second Hospital of Tianjin Medical University, Tianjin, China
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Zhang S, Tang S, Liu Y, Xue B, Xie Q, Zhao L, Yuan H. Protein-bound uremic toxins as therapeutic targets for cardiovascular, kidney, and metabolic disorders. Front Endocrinol (Lausanne) 2025; 16:1500336. [PMID: 39931238 PMCID: PMC11808018 DOI: 10.3389/fendo.2025.1500336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 01/02/2025] [Indexed: 02/13/2025] Open
Abstract
Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic clinical condition characterized by pathological and physiological interactions among metabolic abnormalities, chronic kidney disease, and cardiovascular diseases, leading to multi-organ dysfunction and a higher incidence of cardiovascular endpoints. Traditional approaches to managing CKM syndrome risk are inadequate in these patients, necessitating strategies targeting specific CKM syndrome risk factors. Increasing evidence suggests that addressing uremic toxins and/or pathways induced by uremic toxins may reduce CKM syndrome risk and treat the disease. This review explores the interactions among heart, kidney, and metabolic pathways in the context of uremic toxins and underscores the significant role of uremic toxins as potential therapeutic targets in the pathophysiology of these diseases. Strategies aimed at regulating these uremic toxins offer potential avenues for reversing and managing CKM syndrome, providing new insights for its clinical diagnosis and treatment.
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Affiliation(s)
| | | | | | | | | | | | - Huijuan Yuan
- Department of Endocrinology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Henan Provincial Key Medicine Laboratory of Intestinal Microecology and Diabetes, Zhengzhou, China
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Zhao Y, Jiang Y, Wang F, Sun L, Ding M, Zhang L, Wu B, Zhang X. High glucose promotes macrophage switching to the M1 phenotype via the downregulation of STAT-3 mediated autophagy. PLoS One 2024; 19:e0314974. [PMID: 39739966 DOI: 10.1371/journal.pone.0314974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/20/2024] [Indexed: 01/02/2025] Open
Abstract
AIM Imbalanced M1/M2 macrophage phenotype activation is a key point in diabetic kidney disease (DKD). Macrophages mainly exhibit the M1 phenotype, which contributes to inflammation and fibrosis in DKD. Studies have indicated that autophagy plays an important role in M1/M2 activation. However, the mechanism by which autophagy regulates the macrophage M1/M2 phenotype in DKD is unknown. Thus, the aim of the present study was to explore whether high glucose-induced macrophages switch to the M1 phenotype via the downregulation of STAT-3-mediated autophagy. METHODS DKD model rats were established in vivo via the intraperitoneal injection of streptozocin (STZ). The rats were sacrificed at 18 weeks for histological and molecular analysis. RAW264.7 cells were cultured in vitro with 30 mM glucose in the presence or absence of a STAT-3 activator (colivelin) and an autophagy activator (rapamycin). Moreover, M1 and M2 macrophage activation models were established as a control group. Immunofluorescence and Western blot analyses were used to detect the expression of autophagy-related proteins (LC3 and Beclin-1), M1 markers (iNOS and CD11c) and M2 markers (MR and CD206). RESULTS In DKD, macrophages exhibit an M1 phenotype. Under high-glucose conditions, RAW264.7 macrophages switched to the M1 phenotype. Autophagy was downregulated in high glucose-induced M1 macrophages. Both the STAT-3 activator and the autophagy activator promoted the transition of glucose-induced M1 macrophages to M2 macrophages. Moreover, STAT-3 activation increased the expression of autophagy markers (LC3 and Beclin-1). However, the autophagy activator had no effect on STAT-3 phosphorylation. CONCLUSION High glucose promotes macrophage switching to the M1 phenotype via the downregulation of STAT-3-mediated autophagy.
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Affiliation(s)
- Yu Zhao
- Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing Jiangsu, China
| | - Yuteng Jiang
- Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing Jiangsu, China
| | - Fengmei Wang
- Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing Jiangsu, China
| | - Li Sun
- Department of Nephrology, Xuyi People's Hospital, Huaian, China
| | - Mengyuan Ding
- Department of Nephrology, Xuyi People's Hospital, Huaian, China
| | - Liyuan Zhang
- Department of Nephrology, The First People's Hospital of Lianyungang, Lianyungang, China
| | - Beibei Wu
- Institute of Nephrology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong, China
| | - Xiaoliang Zhang
- Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing Jiangsu, China
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11
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Deng J, Wu P. Integrated bioinformatics analysis and in vivo validation of potential immune-related genes linked to diabetic nephropathy. Heliyon 2024; 10:e40151. [PMID: 39583850 PMCID: PMC11582746 DOI: 10.1016/j.heliyon.2024.e40151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 11/04/2024] [Accepted: 11/04/2024] [Indexed: 11/26/2024] Open
Abstract
Background Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus and the main cause of chronic renal failure. This study explored the potential immunomodulation-related genes (IRGs) in DN using bioinformatics. Methods IRGs were identified using GeneCards, and differentially expressed genes were identified using the GSE99339, GSE96804, and GSE30122 datasets. We conducted enrichment analyses using Gene Ontology, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes to identify the associated signaling pathways. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator regression. The predictive power of IRGs was evaluated using receiver operating characteristic (ROC) curves. Furthermore, we utilized ssGSEA to determine the relative abundance of immune cell infiltration. The expression of five significant IRGs was further validated using immunohistochemistry (IHC) in individuals with DN and real-time PCR (RT-PCR) in animal experiments. Results In total, 17 immunomodulation-related differentially expressed genes were identified, which were enriched in immune-associated pathways and inflammation. GSEA unveiled substantial enrichments in metabolic irregularities and the structural composition of the extracellular matrix. ROC analysis results revealed that the diagnostic efficacy of IFNAR2 and CASP3 was comparatively high. Notably, we identified potential IRGs for DN, including CASP3, LGALS9, and SST, using IHC and RT-PCR. Conclusions CASP3, LGALS9, and SST are potential IRGs in patients with DN. Our findings may offer a theoretical basis for developing more focused and innovative immunotherapy approaches for patients with DN.
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Affiliation(s)
- Jinxiu Deng
- Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, China
- Department of Nephrology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Peiwen Wu
- Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China
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12
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Vinolo E, Maillefer M, Jolly L, Colné N, Meiffren G, Carrasco K, Derive M. The potential of targeting TREM-1 in IBD. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:301-330. [PMID: 39521605 DOI: 10.1016/bs.apha.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Innate immune dysfunction is a hallmark of the pathogenesis of Inflammatory Bowel Disease, both in Crohn's disease and ulcerative colitis. Despite considerable efforts in research to better understand the pathophysiology of IBD and for the development of new therapeutic modalities for IBD patients, there is no therapy specifically targeting the dysregulations of the innate immune response available today in that field. TREM-1 is exclusively expressed by innate immune cells and is an immune amplifier. Its engagement following the primary activation of Pattern Recognition Receptors, including Toll-Like Receptors, triggers the development of a dysregulated and sustained innate immune response, promoting the perpetuation of the inflammatory response in the mucosa of IBD patients, microscopic mucosal tissue alterations, impaired autophagy, impaired epithelial barrier integrity and function, ulcerations, and mucosal damages. In patients, TREM-1 activation is associated with the active status of the disease as well as with severity. Blocking TREM-1 in experimental colitis attenuates the dysregulated innate immune response leading to improved clinical signs. Anti-TREM-1 approaches have the potential of controlling the pathogenic dysregulation of the immune response in IBD by targeting an upstream amplification loop of the activation of innate immunity.
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13
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Sinha SK, Carpio MB, Nicholas SB. Fiery Connections: Macrophage-Mediated Inflammation, the Journey from Obesity to Type 2 Diabetes Mellitus and Diabetic Kidney Disease. Biomedicines 2024; 12:2209. [PMID: 39457523 PMCID: PMC11503991 DOI: 10.3390/biomedicines12102209] [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: 07/15/2024] [Revised: 09/12/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
The high prevalence of diabetes mellitus (DM) poses a significant public health challenge, with diabetic kidney disease (DKD) as one of its most serious consequences. It has become increasingly clear that type 2 DM (T2D) and the complications of DKD are not purely metabolic disorders. This review outlines emerging evidence related to the step-by-step contribution of macrophages to the development and progression of DKD in individuals who specifically develop T2D as a result of obesity. The macrophage is a prominent inflammatory cell that contributes to obesity, where adipocyte hypertrophy leads to macrophage recruitment and eventually to the expansion of adipose tissue. The recruited macrophages secrete proinflammatory cytokines, which cause systemic inflammation, glucose dysregulation, and insulin sensitivity, ultimately contributing to the development of T2D. Under such pathological changes, the kidney is susceptible to elevated glucose and thereby activates signaling pathways that ultimately drive monocyte recruitment. In particular, the early recruitment of proinflammatory macrophages in the diabetic kidney produces inflammatory cytokines/chemokines that contribute to inflammation and tissue damage associated with DKD pathology. Macrophage activation and recruitment are crucial inciting factors that also persist as DKD progresses. Thus, targeting macrophage activation and function could be a promising therapeutic approach, potentially offering significant benefits for managing DKD at all stages of progression.
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Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Maria Beatriz Carpio
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
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14
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Lou Y, Luan YT, Rong WQ, Gai Y. Corilagin alleviates podocyte injury in diabetic nephropathy by regulating autophagy via the SIRT1-AMPK pathway. World J Diabetes 2024; 15:1916-1931. [PMID: 39280180 PMCID: PMC11372637 DOI: 10.4239/wjd.v15.i9.1916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/04/2024] [Accepted: 07/02/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the most frequent chronic microvascular consequence of diabetes, and podocyte injury and malfunction are closely related to the development of DN. Studies have shown that corilagin (Cor) has hepatoprotective, anti-inflammatory, antibacterial, antioxidant, anti-hypertensive, anti-diabetic, and anti-tumor activities. AIM To explore the protective effect of Cor against podocyte injury in DN mice and the underlying mechanisms. METHODS Streptozotocin and a high-fat diet were combined to generate DN mice models, which were then divided into either a Cor group or a DN group (n = 8 in each group). Mice in the Cor group were intraperitoneally injected with Cor (30 mg/kg/d) for 12 wk, and mice in the DN group were treated with saline. Biochemical analysis was used to measure the blood lipid profiles. Hematoxylin and eosin staining was used to detect pathological changes in kidney tissue. Immunohistochemistry and Western blotting were used to assess the protein expression of nephrin and podocin. Mouse podocyte cells (MPC5) were cultured and treated with glucose (5 mmol/L), Cor (50 μM), high glucose (HG) (30 mmol/L), and HG (30 mmol/L) plus Cor (50 μM). Real-time quantitative PCR and Western blotting were performed to examine the effects of Cor on podocyte autophagy. RESULTS Compared with the control group, the DN mice models had increased fasting blood glucose, glycosylated hemoglobin, triglycerides, and total cholesterol, decreased nephrin and podocin expression, increased apoptosis rate, elevated inflammatory cytokines, and enhanced oxidative stress. All of the conditions mentioned above were alleviated after intervention with Cor. In addition, Cor therapy improved SIRT1 and AMPK expression (P < 0.001), inhibited reactive oxygen species and oxidative stress, and elevated autophagy in HG-induced podocytes (P < 0.01). CONCLUSION Cor alleviates podocyte injury by regulating autophagy via the SIRT1-AMPK pathway, thereby exerting its protective impact on renal function in DN mice.
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Affiliation(s)
- Yu Lou
- Department of Preventive Treatment of Disease, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
| | - Yu-Ting Luan
- Department of Infectious Diseases, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
| | - Wen-Qing Rong
- Department of General Practice (Including Medical Oncology), Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
| | - Yun Gai
- Department of General Practice (Including Medical Oncology), Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China
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15
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Guo C, Wang W, Dong Y, Han Y. Identification of key immune-related genes and potential therapeutic drugs in diabetic nephropathy based on machine learning algorithms. BMC Med Genomics 2024; 17:220. [PMID: 39187837 PMCID: PMC11348758 DOI: 10.1186/s12920-024-01995-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 08/19/2024] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a major contributor to chronic kidney disease. This study aims to identify immune biomarkers and potential therapeutic drugs in DN. METHODS We analyzed two DN microarray datasets (GSE96804 and GSE30528) for differentially expressed genes (DEGs) using the Limma package, overlapping them with immune-related genes from ImmPort and InnateDB. LASSO regression, SVM-RFE, and random forest analysis identified four hub genes (EGF, PLTP, RGS2, PTGDS) as proficient predictors of DN. The model achieved an AUC of 0.995 and was validated on GSE142025. Single-cell RNA data (GSE183276) revealed increased hub gene expression in epithelial cells. CIBERSORT analysis showed differences in immune cell proportions between DN patients and controls, with the hub genes correlating positively with neutrophil infiltration. Molecular docking identified potential drugs: cysteamine, eltrombopag, and DMSO. And qPCR and western blot assays were used to confirm the expressions of the four hub genes. RESULTS Analysis found 95 and 88 distinctively expressed immune genes in the two DN datasets, with 14 consistently differentially expressed immune-related genes. After machine learning algorithms, EGF, PLTP, RGS2, PTGDS were identified as the immune-related hub genes associated with DN. In addition, the mRNA and protein levels of them were obviously elevated in HK-2 cells treated with glucose for 24 h, as well as their mRNA expressions in kidney tissues of mice with DN. CONCLUSION This study identified 4 hub immune-related genes (EGF, PLTP, RGS2, PTGDS), as well as their expression profiles and the correlation with immune cell infiltration in DN.
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Affiliation(s)
- Chang Guo
- The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 10086, China.
| | - Wei Wang
- The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 10086, China
| | - Ying Dong
- The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 10086, China
| | - Yubing Han
- The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 10086, China
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16
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Fan Y, Xu Y, Huo Z, Zhang H, Peng L, Jiang X, Thomson AW, Dai H. Role of triggering receptor expressed on myeloid cells-1 in kidney diseases: A biomarker and potential therapeutic target. Chin Med J (Engl) 2024; 137:1663-1673. [PMID: 38809056 PMCID: PMC11268828 DOI: 10.1097/cm9.0000000000003197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Indexed: 05/30/2024] Open
Abstract
ABSTRACT Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.
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Affiliation(s)
- Yuxi Fan
- Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan 410013, China
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ye Xu
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
- Medical College of Guangxi University, Nanning, Guangxi 530004, China
| | - Zhi Huo
- Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan 410013, China
| | - Hedong Zhang
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Longkai Peng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Xin Jiang
- Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People’s Hospital), Zhengzhou, Henan 450000, China
| | - Angus W. Thomson
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Helong Dai
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
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17
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Cliff CL, Squires PE, Hills CE. Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease. Cell Commun Signal 2024; 22:351. [PMID: 38970061 PMCID: PMC11225428 DOI: 10.1186/s12964-024-01728-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/26/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Accompanied by activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, aberrant connexin 43 (Cx43) hemichannel-mediated ATP release is situated upstream of inflammasome assembly and inflammation and contributes to multiple secondary complications of diabetes and associated cardiometabolic comorbidities. Evidence suggests there may be a link between Cx43 hemichannel activity and inflammation in the diabetic kidney. The consequences of blocking tubular Cx43 hemichannel-mediated ATP release in priming/activation of the NLRP3 inflammasome in a model of diabetic kidney disease (DKD) was investigated. We examined downstream markers of inflammation and the proinflammatory and chemoattractant role of the tubular secretome on macrophage recruitment and activation. METHODS Analysis of human transcriptomic data from the Nephroseq repository correlated gene expression to renal function in DKD. Primary human renal proximal tubule epithelial cells (RPTECs) and monocyte-derived macrophages (MDMs) were cultured in high glucose and inflammatory cytokines as a model of DKD to assess Cx43 hemichannel activity, NLRP3 inflammasome activation and epithelial-to-macrophage paracrine-mediated crosstalk. Tonabersat assessed a role for Cx43 hemichannels. RESULTS Transcriptomic analysis from renal biopsies of patients with DKD showed that increased Cx43 and NLRP3 expression correlated with declining glomerular filtration rate (GFR) and increased proteinuria. In vitro, Tonabersat blocked glucose/cytokine-dependant increases in Cx43 hemichannel-mediated ATP release and reduced expression of inflammatory markers and NLRP3 inflammasome activation in RPTECs. We observed a reciprocal relationship in which NLRP3 activity exacerbated increased Cx43 expression and hemichannel-mediated ATP release, events driven by nuclear factor kappa-B (NFκB)-mediated priming and Cx43 hemichannel opening, changes blocked by Tonabersat. Conditioned media (CM) from RPTECs treated with high glucose/cytokines increased expression of inflammatory markers in MDMs, an effect reduced when macrophages were pre-treated with Tonabersat. Co-culture using conditioned media from Tonabersat-treated RPTECs dampened macrophage inflammatory marker expression and reduced macrophage migration. CONCLUSION Using a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes.
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Affiliation(s)
- C L Cliff
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK
| | - P E Squires
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK
| | - C E Hills
- Joseph Banks Laboratories, School of Life and Environmental Sciences, University of Lincoln, Lincoln, LN6 7DL, UK.
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18
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Islamuddin M, Qin X. Renal macrophages and NLRP3 inflammasomes in kidney diseases and therapeutics. Cell Death Discov 2024; 10:229. [PMID: 38740765 PMCID: PMC11091222 DOI: 10.1038/s41420-024-01996-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/22/2024] [Accepted: 04/26/2024] [Indexed: 05/16/2024] Open
Abstract
Macrophages are exceptionally diversified cell types and perform unique features and functions when exposed to different stimuli within the specific microenvironment of various kidney diseases. In instances of kidney tissue necrosis or infection, specific patterns associated with damage or pathogens prompt the development of pro-inflammatory macrophages (M1). These M1 macrophages contribute to exacerbating tissue damage, inflammation, and eventual fibrosis. Conversely, anti-inflammatory macrophages (M2) arise in the same circumstances, contributing to kidney repair and regeneration processes. Impaired tissue repair causes fibrosis, and hence macrophages play a protective and pathogenic role. In response to harmful stimuli within the body, inflammasomes, complex assemblies of multiple proteins, assume a pivotal function in innate immunity. The initiation of inflammasomes triggers the activation of caspase 1, which in turn facilitates the maturation of cytokines, inflammation, and cell death. Macrophages in the kidneys possess the complete elements of the NLRP3 inflammasome, including NLRP3, ASC, and pro-caspase-1. When the NLRP3 inflammasomes are activated, it triggers the activation of caspase-1, resulting in the release of mature proinflammatory cytokines (IL)-1β and IL-18 and cleavage of Gasdermin D (GSDMD). This activation process therefore then induces pyroptosis, leading to renal inflammation, cell death, and renal dysfunction. The NLRP3-ASC-caspase-1-IL-1β-IL-18 pathway has been identified as a factor in the development of the pathophysiology of numerous kidney diseases. In this review, we explore current progress in understanding macrophage behavior concerning inflammation, injury, and fibrosis in kidneys. Emphasizing the pivotal role of activated macrophages in both the advancement and recovery phases of renal diseases, the article delves into potential strategies to modify macrophage functionality and it also discusses emerging approaches to selectively target NLRP3 inflammasomes and their signaling components within the kidney, aiming to facilitate the healing process in kidney diseases.
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Affiliation(s)
- Mohammad Islamuddin
- Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University School of Medicine, Tulane University, 18703 Three Rivers Road, Covington, LA, 70433, USA.
- Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
| | - Xuebin Qin
- Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University School of Medicine, Tulane University, 18703 Three Rivers Road, Covington, LA, 70433, USA.
- Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
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Zhou TY, Tian N, Li L, Yu R. Iridoids modulate inflammation in diabetic kidney disease: A review. JOURNAL OF INTEGRATIVE MEDICINE 2024; 22:210-222. [PMID: 38631983 DOI: 10.1016/j.joim.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 02/18/2024] [Indexed: 04/18/2024]
Abstract
In recent years, preclinical research on diabetic kidney disease (DKD) has surged to the forefront of scientific and clinical attention. DKD has become a pervasive complication of type 2 diabetes. Given the complexity of its etiology and pathological mechanisms, current interventions, including drugs, dietary modifications, exercise, hypoglycemic treatments and lipid-lowering methods, often fall short in achieving desired therapeutic outcomes. Iridoids, primarily derived from the potent components of traditional herbs, have been the subject of long-standing research. Preclinical data suggest that iridoids possess notable renal protective properties; however, there has been no summary of the research on their efficacy in the management and treatment of DKD. This article consolidates findings from in vivo and in vitro research on iridoids in the context of DKD and highlights their shared anti-inflammatory activities in treating this condition. Additionally, it explores how certain iridoid components modify their chemical structures through the regulation of intestinal flora, potentially bolstering their therapeutic effects. This review provides a focused examination of the mechanisms through which iridoids may prevent or treat DKD, offering valuable insights for future research endeavors. Please cite this article as: Zhou TY, Tian N, Li L, Yu R. Iridoids modulate inflammation in diabetic kidney disease: A review. J Integr Med. 2024; 22(3): 210-222.
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Affiliation(s)
- Tong-Yi Zhou
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Na Tian
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Liu Li
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Rong Yu
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China; Hunan Provincial Key Laboratory of Translational Research in Traditional Chinese Medicine Prescriptions and Zheng, Changsha 410208, Hunan Province, China.
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20
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Peng QY, An Y, Jiang ZZ, Xu Y. The Role of Immune Cells in DKD: Mechanisms and Targeted Therapies. J Inflamm Res 2024; 17:2103-2118. [PMID: 38601771 PMCID: PMC11005934 DOI: 10.2147/jir.s457526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 03/19/2024] [Indexed: 04/12/2024] Open
Abstract
Diabetic kidney disease (DKD), is a common microvascular complication and a major cause of death in patients with diabetes. Disorders of immune cells and immune cytokines can accelerate DKD development of in a number of ways. As the kidney is composed of complex and highly differentiated cells, the interactions among different cell types and immune cells play important regulatory roles in disease development. Here, we summarize the latest research into the molecular mechanisms underlying the interactions among various immune and renal cells in DKD. In addition, we discuss the most recent studies related to single cell technology and bioinformatics analysis in the field of DKD. The aims of our review were to explore immune cells as potential therapeutic targets in DKD and provide some guidance for future clinical treatments.
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Affiliation(s)
- Qiu-Yue Peng
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, People’s Republic of China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People’s Republic of China
| | - Ying An
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, People’s Republic of China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People’s Republic of China
| | - Zong-Zhe Jiang
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, People’s Republic of China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People’s Republic of China
| | - Yong Xu
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, People’s Republic of China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People’s Republic of China
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Youssef N, Noureldein MH, Riachi ME, Haddad A, Eid AA. Macrophage polarization and signaling in diabetic kidney disease: a catalyst for disease progression. Am J Physiol Renal Physiol 2024; 326:F301-F312. [PMID: 38153850 DOI: 10.1152/ajprenal.00266.2023] [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: 08/30/2023] [Revised: 11/29/2023] [Accepted: 12/16/2023] [Indexed: 12/30/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes affecting millions of people worldwide. Macrophages, a critical immune cell type, are central players in the development and progression of DKD. In this comprehensive review, we delve into the intricate role of macrophages in DKD, examining how they can become polarized into proinflammatory M1 or anti-inflammatory M2 phenotypes. We explore the signaling pathways involved in macrophage recruitment and polarization in the kidneys, including the key cytokines and transcription factors that promote M1 and M2 polarization. In addition, we discuss the latest clinical studies investigating macrophages in DKD and explore the potential of hypoglycemic drugs for modulating macrophage polarization. By gaining a deeper understanding of the mechanisms that regulate macrophage polarization in DKD, we may identify novel therapeutic targets for this debilitating complication of diabetes. This review provides valuable insights into the complex interplay between macrophages and DKD, shedding light on the latest developments in this important area of research. This review aims to enhance understanding of the role that macrophages play in the pathogenesis of DKD.
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Affiliation(s)
- Natalie Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamed H Noureldein
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mansour E Riachi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Antony Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
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22
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Chen L, Lu S, Wu Z, Zhang E, Cai Q, Zhang X. Innate immunity in diabetic nephropathy: Pathogenic mechanisms and therapeutic targets. MEDCOMM – FUTURE MEDICINE 2024; 3. [DOI: 10.1002/mef2.76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 02/18/2024] [Indexed: 01/02/2025]
Abstract
AbstractDiabetic nephropathy (DN) represents a prevalent chronic microvascular complication of diabetes mellitus (DM) and is a major cause of end‐stage renal disease. The anfractuous surrounding of DN pathogenesis and the intricate nature of this metabolic disorder often pose challenges in both the diagnosis and treatment of DN compared to other kidney diseases. Hyperglycaemia in DM predispose vulnerable renal cells into microenvironmental disequilibrium and thereby results in innate immunocytes infiltration including neutrophils, macrophages, myeloid‐derived suppressor cells, dendritic cells, and so forth. These immune cells play dual roles in kidney injury and closely correlated with the degree of proteinuria in DN patients. Additionally, innate immune signaling cascades, initiated by altered metabolic and hemodynamic in diabetic context, are crucial in instigating and perpetuating renal inflammation, which detrimentally contribute to DN pathogenesis. As such, anti‐inflammatory therapies, particularly those targeting innate immunity, hold renoprotective promise in DN. In this article, we reviewed the origin and feature of the above four prominent kidney innate immune cells, analyze their pathogenic role in DN, and discuss potential targeted‐therapeutic strategies, aiming to enhance the current understanding of renal innate immunity and hence help to discover promising therapeutic approaches for DN.
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Affiliation(s)
- Le‐Xin Chen
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Shu‐Ru Lu
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Zhi‐Hao Wu
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - En‐Xin Zhang
- Shenzhen Bao'an Authentic TCM Therapy Hospital Shenzhen PR China
| | - Qing‐Qun Cai
- The First Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Xiao‐Jun Zhang
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
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23
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Reynolds L, Luo Z, Singh K. Diabetic complications and prospective immunotherapy. Front Immunol 2023; 14:1219598. [PMID: 37483613 PMCID: PMC10360133 DOI: 10.3389/fimmu.2023.1219598] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/22/2023] [Indexed: 07/25/2023] Open
Abstract
The incidence of Diabetes Mellitus is increasing globally. Individuals who have been burdened with diabetes for many years often develop complications as a result of hyperglycemia. More and more research is being conducted highlighting inflammation as an important factor in disease progression. In all kinds of diabetes, hyperglycemia leads to activation of alternative glucose metabolic pathways, resulting in problematic by-products including reactive oxygen species and advanced glycation end products. This review takes a look into the pathogenesis of three specific diabetic complications; retinopathy, nephropathy and neuropathy as well as their current treatment options. By considering recent research papers investigating the effects of immunotherapy on relevant conditions in animal models, multiple strategies are suggested for future treatment and prevention of diabetic complications with an emphasis on molecular targets associated with the inflammation.
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Yan J, Li X, Liu N, He JC, Zhong Y. Relationship between Macrophages and Tissue Microenvironments in Diabetic Kidneys. Biomedicines 2023; 11:1889. [PMID: 37509528 PMCID: PMC10377233 DOI: 10.3390/biomedicines11071889] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/23/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Increasing evidence has suggested that inflammation is a key microenvironment involved in the development and progression of DN. Studies have confirmed that macrophage accumulation is closely related to the progression to human DN. Macrophage phenotype is highly regulated by the surrounding microenvironment in the diabetic kidneys. M1 and M2 macrophages represent distinct and sometimes coexisting functional phenotypes of the same population, with their roles implicated in pathological changes, such as in inflammation and fibrosis associated with the stage of DN. Recent findings from single-cell RNA sequencing of macrophages in DN further confirmed the heterogeneity and plasticity of the macrophages. In addition, intrinsic renal cells interact with macrophages directly or through changes in the tissue microenvironment. Macrophage depletion, modification of its polarization, and autophagy could be potential new therapies for DN.
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Affiliation(s)
- Jiayi Yan
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xueling Li
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ni Liu
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - John Cijiang He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yifei Zhong
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Asadollahi S, Hadizadeh M, Namiranian N, Kalantar SM, Firoozabadi AD, Injinari N. Misexpression of LINC01410, FOSL1, and MAFB in peripheral blood mononuclear cells associated with diabetic nephropathy. Gene 2023; 862:147265. [PMID: 36764337 DOI: 10.1016/j.gene.2023.147265] [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: 10/26/2022] [Revised: 01/23/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023]
Abstract
AIMS Currently, diabetic nephropathy (DN) is considered the leading cause of the end-stage renal disease (ESRD). However, its specific molecular mechanism is still unclear, and there is still a lack of effective diagnostic and therapeutic methods. METHOD A pathway was assumed after bioinformatics analysis of GEO datasets related to individuals with various levels of DN, LINC01410, MAFB, and FOSL1. Then, 46 patients with type 2 diabetes (T2DM) and different levels of albuminuria, and 12 individuals without diabetes, were selected. qPCR was performed to evaluate gene expression. One-way ANOVA followed by Tukey's -and linear trend tests were performed to analyze gene expression in different stages of the disease. Moreover, receiver operating characteristic (ROC) curves and the correlation between LINC01410, FOSL1, and MAFB were analyzed. RESULTS LINC01410, MAFB, and FOSL1 were selected based on bioinformatics analyses. The qPCR results showed that the expression of LINC01410 decreased, and FOSL1 and MAFB increased in micro-and macroalbuminuria groups compared to normoalbuminuria groups (P < 0.05). ROC curves demonstrated a significant diagnostic accuracy of LINC01410, MAFB, and FOSL1 between DN and participants with normoalbuminuria (P < 0.05). Pearson's correlation analysis revealed a positive association between the expressions of FOSL1 and MAFB (p = 0.01, r = 0.39). However, there was no correlation between LINC01410 with MAFB and FOSL1 (p = 0.23 and p = 0.21, respectively). CONCLUSION Dysregulation of LINC01410, MAFB, and FOSL1 is related to DN. These results may provide new insights into the role of LINC01410, MAFB, and FOSL1 as potential biomarkers in DN.
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Affiliation(s)
- Samira Asadollahi
- Research Center for Food Hygiene and Safety, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Morteza Hadizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Nasim Namiranian
- Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Mehdi Kalantar
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Meybod Genetic Research Center, Meybod, Yazd, Iran
| | - Ali Dehghani Firoozabadi
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nastaran Injinari
- Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Infante B, Conserva F, Pontrelli P, Leo S, Stasi A, Fiorentino M, Troise D, dello Strologo A, Alfieri C, Gesualdo L, Castellano G, Stallone G. Recent advances in molecular mechanisms of acute kidney injury in patients with diabetes mellitus. Front Endocrinol (Lausanne) 2023; 13:903970. [PMID: 36686462 PMCID: PMC9849571 DOI: 10.3389/fendo.2022.903970] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023] Open
Abstract
Several insults can lead to acute kidney injury (AKI) in native kidney and transplant patients, with diabetes critically contributing as pivotal risk factor. High glucose per se can disrupt several signaling pathways within the kidney that, if not restored, can favor the instauration of mechanisms of maladaptive repair, altering kidney homeostasis and proper function. Diabetic kidneys frequently show reduced oxygenation, vascular damage and enhanced inflammatory response, features that increase the kidney vulnerability to hypoxia. Importantly, epidemiologic data shows that previous episodes of AKI increase susceptibility to diabetic kidney disease (DKD), and that patients with DKD and history of AKI have a generally worse prognosis compared to DKD patients without AKI; it is therefore crucial to monitor diabetic patients for AKI. In the present review, we will describe the causes that contribute to increased susceptibility to AKI in diabetes, with focus on the molecular mechanisms that occur during hyperglycemia and how these mechanisms expose the different types of resident renal cells to be more vulnerable to maladaptive repair during AKI (contrast- and drug-induced AKI). Finally, we will review the list of the existing candidate biomarkers of diagnosis and prognosis of AKI in patients with diabetes.
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Affiliation(s)
- Barbara Infante
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Francesca Conserva
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Paola Pontrelli
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Serena Leo
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Dario Troise
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Carlo Alfieri
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Wang AJ, Wang A, Hascall V. Heparin binding proteins on monocyte cell surfaces regulates pre-inflammatory responses in diabetes. JOURNAL OF ALLERGY AND INFECTIOUS DISEASES 2023; 4:16-23. [PMID: 38618493 PMCID: PMC11013956 DOI: 10.46439/allergy.4.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Many diabetic complications, such as renal and cardiovascular disease, share a common association with extensive and chronic inflammation due to infiltration by activated leukocytes that originate from the bone marrow (BM). Our previous study demonstrated that macrophage progenitor cells that divided in hyperglycemia induced intracellular synthesis of hyaluronan and became pro-inflammatory macrophages (Mpi), and that the presence of low concentrations of heparin (~50 nM) prevented the intracellular HA synthesis and promoted the formation of tissue repair macrophages (Mtr). However, the molecular mechanism underlying heparin's role is still unknown. This study showed that heparin can be internalized by dividing monocyte progenitor cells. Further, there are two most abundant heparin binding proteins, alpha-enolase (ENO-1) and cofilin-1, identified on monocyte cell surfaces. In addition to their conventional roles inside of cells, ENO-1 and cofilin-1 can be found on cell surfaces and are also involved in autoimmune diseases. Thus, this study provides new insight into heparin's role in regulating monocyte and macrophage function.
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Affiliation(s)
- Andrew Jun Wang
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195, USA
| | - Aimin Wang
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195, USA
| | - Vincent Hascall
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Liang M, Zhu X, Zhang D, He W, Zhang J, Yuan S, He Q, Jin J. Yi-Shen-Hua-Shi granules inhibit diabetic nephropathy by ameliorating podocyte injury induced by macrophage-derived exosomes. Front Pharmacol 2022; 13:962606. [PMID: 36506555 PMCID: PMC9732029 DOI: 10.3389/fphar.2022.962606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022] Open
Abstract
Objective: To observe the therapeutic effect of Yi-Shen-Hua-Shi (YSHS) granule in podocyte damage and diabetic nephropathy (DN) proteinuria and to explore the corresponding mechanism. Methods: The db/db mice were used to establish the DN model. Serum creatinine (SCr), blood urea nitrogen (BUN), and 24 h urinary proteinuria were detected with specific kits. Glomerular structural lesions and podocyte apoptosis were detected through HE staining, TUNEL assay, and immunofluorescence. The medicated serum of YSHS granule (YSHS-serum) or control serum was prepared. Macrophage-derived exosomes were extracted using an exosome extraction kit. Morphology and the protein concentration of exosomes were evaluated by a transmission electron microscope (TEM) and BCA kit. The activity and apoptosis of podocyte MPC5 cells, the M1 macrophage polarization, and the protein expression of an exosome marker and cleaved caspase were detected by the CCK8 experiment, flow cytometry, and Western blot, respectively. The miR-21a-5p expression in podocytes and the exosomes from macrophages were measured by qRT-PCR. The effect of YSHS granule on the infiltration of M1 macrophages in the kidney tissue in db/db mice was measured by immunofluorescence. Results: The YSHS granule could improve renal function, reduce proteinuria, and inhibit glomerular structural lesions and podocyte apoptosis in db/db mice. High-glucose (HG) stimulation and YSHS granule treatment did not affect the protein concentration in macrophage-derived exosomes. Macrophage-derived exosomes could inhibit the cell viability and increase apoptosis of podocytes, especially the exosomes from macrophages treated with HG and control serum. Compared with the exosomes secreted by macrophages after an HG treatment, the exosome from macrophages treated with HG and YSHS granule showed lower inhibitory effects on podocyte activity, accompanied by the decreased upregulating effects of macrophage-derived exosomes on the miR-21a-5p in podocytes. miR-21a-5p mimics could reduce podocyte activity and promote caspase-3 shearing. M1 polarization of macrophages could change the content of miR-21a-5p in macrophage-derived exosomes. In addition, YSHS granule could inhibit HG-induced M1 polarization of macrophages and M1 macrophage infiltration in renal tissues. Conclusion: The YSHS granule could improve the podocyte injury induced by macrophage-derived exosomes and alleviate the progression of DN. This regulation might be related to the inhibition of M1 macrophage polarization by YSHS granule and the reduction of the miR-21a-5p content in macrophage-derived exosomes.
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Affiliation(s)
- Mingzhu Liang
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China,Department of Nephrology, The Medical College of Qingdao University, Qingdao, China
| | - Xiaodong Zhu
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Di Zhang
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Wenfang He
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Jinshi Zhang
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Shizhu Yuan
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Qiang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China,*Correspondence: Qiang He, ; Juan Jin,
| | - Juan Jin
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China,*Correspondence: Qiang He, ; Juan Jin,
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Li HD, You YK, Shao BY, Wu WF, Wang YF, Guo JB, Meng XM, Chen H. Roles and crosstalks of macrophages in diabetic nephropathy. Front Immunol 2022; 13:1015142. [PMID: 36405700 PMCID: PMC9666695 DOI: 10.3389/fimmu.2022.1015142] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/20/2022] [Indexed: 11/05/2022] Open
Abstract
Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages.
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Affiliation(s)
- Hai-Di Li
- Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yong-Ke You
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China
| | - Bao-Yi Shao
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wei-Feng Wu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yi-Fan Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jian-Bo Guo
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- *Correspondence: Haiyong Chen, ; Xiao-Ming Meng,
| | - Haiyong Chen
- Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Haiyong Chen, ; Xiao-Ming Meng,
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Siskind S, Zhang F, Brenner M, Wang P. Extracellular CIRP induces acute kidney injury via endothelial TREM-1. Front Physiol 2022; 13:954815. [PMID: 36246143 PMCID: PMC9558214 DOI: 10.3389/fphys.2022.954815] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/12/2022] [Indexed: 11/20/2022] Open
Abstract
Introduction: Acute kidney injury is associated with elevated serum levels of extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern released during ischemia/reperfusion injury, hemorrhagic shock, and sepsis. It is unknown if circulating eCIRP and eCIRP-induced activation of receptor triggering receptor expressed on myeloid cells-1 (TREM-1), expressed on endothelial cells, play an important role in the pathogenesis of AKI. Methods: Male B6 wild-type (WT) and TREM-1−/− mice were subjected to intravenous injection of recombinant murine (rm) CIRP. Serum, urine, and renal tissue were collected 6 h later for analysis. Additionally, primary human renal glomerular endothelial cells (HRGEC) were stimulated in vitro with rmCIRP after pretreatment with M3, a novel inhibitory peptide of TREM-1, or vehicle. Supernatants and cells were collected 20 h after stimulation. Results: After injection with rmCIRP, WT mice had a significant increase in serum levels of BUN, creatinine, and NGAL compared to control. Additionally, NGAL was significantly increased in the urine of rmCIRP-injected mice, suggesting that circulating eCIRP can directly induce AKI. The levels of TREM-1 mRNA in the kidneys, as well as soluble (s) TREM-1 released into the serum and urine, were significantly increased in rmCIRP-injected mice. TREM-1−/− mice injected with rmCIRP had attenuated AKI, indicated by significantly decreased serum BUN, creatinine, and NGAL, and renal mRNA expression of NGAL and KIM-1 compared to WT mice. TREM-1−/− mice also had attenuated endothelial activation, with decreased mRNA and protein expression of ICAM-1 in renal tissue. HRGEC stimulated with rmCIRP in vitro had significant increases in cytokine production and sTREM-1 release, which was attenuated in cells treated with M3. Conclusion: Activation of renal TREM-1 with circulating eCIRP is sufficient to cause AKI. Elevated levels of eCIRP may be critical for the development of AKI under conditions such as ischemia/reperfusion injury, hemorrhagic shock, and sepsis. Mice deficient in the TREM-1 receptor have attenuated AKI and reduced endothelial cell activation after injection of rmCIRP. TREM-1 inhibition with M3 attenuates HRGEC activation after eCIRP stimulation. Targeting eCIRP activation of TREM-1 may provide a novel and effective treatment for AKI.
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Affiliation(s)
- Sara Siskind
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Elmezzi Graduate School of Medicine, Manhasset, NY, United States
| | - Fangming Zhang
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Max Brenner
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Elmezzi Graduate School of Medicine, Manhasset, NY, United States
- *Correspondence: Ping Wang, ; Max Brenner,
| | - Ping Wang
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Elmezzi Graduate School of Medicine, Manhasset, NY, United States
- *Correspondence: Ping Wang, ; Max Brenner,
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Fu S, Cheng Y, Wang X, Huang J, Su S, Wu H, Yu J, Xu Z. Identification of diagnostic gene biomarkers and immune infiltration in patients with diabetic kidney disease using machine learning strategies and bioinformatic analysis. Front Med (Lausanne) 2022; 9:918657. [PMID: 36250071 PMCID: PMC9556813 DOI: 10.3389/fmed.2022.918657] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
Objective Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Early diagnosis is critical to prevent its progression. The aim of this study was to identify potential diagnostic biomarkers for DKD, illustrate the biological processes related to the biomarkers and investigate the relationship between them and immune cell infiltration. Materials and methods Gene expression profiles (GSE30528, GSE96804, and GSE99339) for samples obtained from DKD and controls were downloaded from the Gene Expression Omnibus database as a training set, and the gene expression profiles (GSE47185 and GSE30122) were downloaded as a validation set. Differentially expressed genes (DEGs) were identified using the training set, and functional correlation analyses were performed. The least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forests (RF) were performed to identify potential diagnostic biomarkers. To evaluate the diagnostic efficacy of these potential biomarkers, receiver operating characteristic (ROC) curves were plotted separately for the training and validation sets, and immunohistochemical (IHC) staining for biomarkers was performed in the DKD and control kidney tissues. In addition, the CIBERSORT, XCELL and TIMER algorithms were employed to assess the infiltration of immune cells in DKD, and the relationships between the biomarkers and infiltrating immune cells were also investigated. Results A total of 95 DEGs were identified. Using three machine learning algorithms, DUSP1 and PRKAR2B were identified as potential biomarker genes for the diagnosis of DKD. The diagnostic efficacy of DUSP1 and PRKAR2B was assessed using the areas under the curves in the ROC analysis of the training set (0.945 and 0.932, respectively) and validation set (0.789 and 0.709, respectively). IHC staining suggested that the expression levels of DUSP1 and PRKAR2B were significantly lower in DKD patients compared to normal. Immune cell infiltration analysis showed that B memory cells, gamma delta T cells, macrophages, and neutrophils may be involved in the development of DKD. Furthermore, both of the candidate genes are associated with these immune cell subtypes to varying extents. Conclusion DUSP1 and PRKAR2B are potential diagnostic markers of DKD, and they are closely associated with immune cell infiltration.
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Affiliation(s)
- Shaojie Fu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Yanli Cheng
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Xueyao Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Jingda Huang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Sensen Su
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Hao Wu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Jinyu Yu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Zhonggao Xu,
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Chen J, Liu Q, He J, Li Y. Immune responses in diabetic nephropathy: Pathogenic mechanisms and therapeutic target. Front Immunol 2022; 13:958790. [PMID: 36045667 PMCID: PMC9420855 DOI: 10.3389/fimmu.2022.958790] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/28/2022] [Indexed: 11/14/2022] Open
Abstract
Diabetic nephropathy (DN) is a chronic, inflammatory disease affecting millions of diabetic patients worldwide. DN is associated with proteinuria and progressive slowing of glomerular filtration, which often leads to end-stage kidney diseases. Due to the complexity of this metabolic disorder and lack of clarity about its pathogenesis, it is often more difficult to diagnose and treat than other kidney diseases. Recent studies have highlighted that the immune system can inadvertently contribute to DN pathogenesis. Cells involved in innate and adaptive immune responses can target the kidney due to increased expression of immune-related localization factors. Immune cells then activate a pro-inflammatory response involving the release of autocrine and paracrine factors, which further amplify inflammation and damage the kidney. Consequently, strategies to treat DN by targeting the immune responses are currently under study. In light of the steady rise in DN incidence, this timely review summarizes the latest findings about the role of the immune system in the pathogenesis of DN and discusses promising preclinical and clinical therapies.
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Affiliation(s)
| | | | - Jinhan He
- *Correspondence: Jinhan He, ; Yanping Li,
| | - Yanping Li
- *Correspondence: Jinhan He, ; Yanping Li,
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Jia Y, Chen J, Zheng Z, Tao Y, Zhang S, Zou M, Yang Y, Xue M, Hu F, Li Y, Zhang Q, Xue Y, Zheng Z. Tubular epithelial cell-derived extracellular vesicles induce macrophage glycolysis by stabilizing HIF-1α in diabetic kidney disease. Mol Med 2022; 28:95. [PMID: 35962319 PMCID: PMC9373297 DOI: 10.1186/s10020-022-00525-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 08/04/2022] [Indexed: 11/20/2022] Open
Abstract
Background Albuminuria is a hallmark of diabetic kidney disease (DKD) that promotes its progression, leading to renal fibrosis. Renal macrophage function is complex and influenced by macrophage metabolic status. However, the metabolic state of diabetic renal macrophages and the impact of albuminuria on the macrophage metabolic state are poorly understood. Methods Extracellular vesicles (EVs) from tubular epithelial cells (HK-2) were evaluated using transmission electron microscopy, nanoparticle tracking analysis and western blotting. Glycolytic enzyme expression in macrophages co-cultured with HSA-treated HK-2 cell-derived EVs was detected using RT-qPCR and western blotting. The potential role of EV-associated HIF-1α in the mediation of glycolysis was explored in HIF-1α siRNA pre-transfected macrophages co-cultured with HSA-treated HK-2 cell-derived EVs, and the extent of HIF-1α hydroxylation was measured using western blotting. Additionally, we injected db/db mice with EVs via the caudal vein twice a week for 4 weeks. Renal macrophages were isolated using CD11b microbeads, and immunohistofluorescence was applied to confirm the levels of glycolytic enzymes and HIF-1α in these macrophages. Results Glycolysis was activated in diabetic renal macrophages after co-culture with HSA-treated HK-2 cells. Moreover, HSA-treated HK-2 cell-derived EVs promoted macrophage glycolysis both in vivo and in vitro. Inhibition of glycolysis activation in macrophages using the glycolysis inhibitor 2-DG decreased the expression of both inflammatory and fibrotic genes. Mechanistically, EVs from HSA-stimulated HK-2 cells were found to accelerate macrophage glycolysis by stabilizing HIF-1α. We also found that several miRNAs and lncRNAs, which have been reported to stabilize HIF-1α expression, were increased in HSA-treated HK-2 cell-derived EVs. Conclusion Our study suggested that albuminuria induced renal macrophage glycolysis through tubular epithelial cell-derived EVs by stabilizing HIF-1α, indicating that regulation of macrophage glycolysis may offer a new treatment strategy for DKD patients, especially those with macroalbuminuria. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00525-1.
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Affiliation(s)
- Yijie Jia
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiaqi Chen
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhikang Zheng
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yuan Tao
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shuting Zhang
- Department of Endocrinology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Meina Zou
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yanlin Yang
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Meng Xue
- Department of Endocrinology and Metabolism, Shenzhen People's Hospital (The Second Clinical Medical College, The First Affiliated Hospital, Southern University of Science and Technology), Jinan University, Shenzhen, China
| | - Fang Hu
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Yang Li
- Department of Geriatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Zhang
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yaoming Xue
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Zongji Zheng
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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Tian F, Chen H, Zhang J, He W. Reprogramming Metabolism of Macrophages as a Target for Kidney Dysfunction Treatment in Autoimmune Diseases. Int J Mol Sci 2022; 23:8024. [PMID: 35887371 PMCID: PMC9316004 DOI: 10.3390/ijms23148024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 12/04/2022] Open
Abstract
Chronic kidney disease (CKD), as one of the main complications of many autoimmune diseases, is difficult to cure, which places a huge burden on patients' health and the economy and poses a great threat to human health. At present, the mainstream view is that autoimmune diseases are a series of diseases and complications caused by immune cell dysfunction leading to the attack of an organism's tissues by its immune cells. The kidney is the organ most seriously affected by autoimmune diseases as it has a very close relationship with immune cells. With the development of an in-depth understanding of cell metabolism in recent years, an increasing number of scientists have discovered the metabolic changes in immune cells in the process of disease development, and we have a clearer understanding of the characteristics of the metabolic changes in immune cells. This suggests that the regulation of immune cell metabolism provides a new direction for the treatment and prevention of kidney damage caused by autoimmune diseases. Macrophages are important immune cells and are a double-edged sword in the repair process of kidney injury. Although they can repair damaged kidney tissue, over-repair will also lead to the loss of renal structural reconstruction function. In this review, from the perspective of metabolism, the metabolic characteristics of macrophages in the process of renal injury induced by autoimmune diseases are described, and the metabolites that can regulate the function of macrophages are summarized. We believe that treating macrophage metabolism as a target can provide new ideas for the treatment of the renal injury caused by autoimmune diseases.
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Affiliation(s)
- Feng Tian
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
| | - Hui Chen
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Tianjin 100730, China
| | - Jianmin Zhang
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
- Haihe Laboratory of Cell Ecosystem, Tianjin 100730, China
| | - Wei He
- Department of Immunology, CAMS Key Laboratory T Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
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Wei R, Qiao J, Cui D, Pan Q, Guo L. Screening and Identification of Hub Genes in the Development of Early Diabetic Kidney Disease Based on Weighted Gene Co-Expression Network Analysis. Front Endocrinol (Lausanne) 2022; 13:883658. [PMID: 35721731 PMCID: PMC9204256 DOI: 10.3389/fendo.2022.883658] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/13/2022] [Indexed: 11/21/2022] Open
Abstract
Objective The study aimed to screen key genes in early diabetic kidney disease (DKD) and predict their biological functions and signaling pathways using bioinformatics analysis of gene chips interrelated to early DKD in the Gene Expression Omnibus database. Methods Gene chip data for early DKD was obtained from the Gene Expression Omnibus expression profile database. We analyzed differentially expressed genes (DEGs) between patients with early DKD and healthy controls using the R language. For the screened DEGs, we predicted the biological functions and relevant signaling pathways by enrichment analysis of Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using the STRING database and Cytoscape software, we constructed a protein interaction network to screen hub pathogenic genes. Finally, we performed immunohistochemistry on kidney specimens from the Beijing Hospital to verify the above findings. Results A total of 267 differential genes were obtained using GSE142025, namely, 176 upregulated and 91 downregulated genes. GO functional annotation enrichment analysis indicated that the DEGs were mainly involved in immune inflammatory response and cytokine effects. KEGG pathway analysis indicated that C-C receptor interactions and the IL-17 signaling pathway are essential for early DKD. We identified FOS, EGR1, ATF3, and JUN as hub sites of protein interactions using a protein-protein interaction network and module analysis. We performed immunohistochemistry (IHC) on five samples of early DKD and three normal samples from the Beijing Hospital to label the proteins. This demonstrated that FOS, EGR1, ATF3, and JUN in the early DKD group were significantly downregulated. Conclusion The four hub genes FOS, EGR1, ATF3, and JUN were strongly associated with the infiltration of monocytes, M2 macrophages, and T regulatory cells in early DKD samples. We revealed that the expression of immune response or inflammatory genes was suppressed in early DKD. Meanwhile, the FOS group of low-expression genes showed that the activated biological functions included mRNA methylation, insulin receptor binding, and protein kinase A binding. These genes and pathways may serve as potential targets for treating early DKD.
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Affiliation(s)
- Ran Wei
- Department of Endocrinology, Peking University Fifth School of Clinical Medicine, Beijing, China
| | - Jingtao Qiao
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Di Cui
- Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Qi Pan
- Department of Endocrinology, Peking University Fifth School of Clinical Medicine, Beijing, China
| | - Lixin Guo
- Department of Endocrinology, Peking University Fifth School of Clinical Medicine, Beijing, China
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Cliff CL, Williams BM, Chadjichristos CE, Mouritzen U, Squires PE, Hills CE. Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes. Int J Mol Sci 2022; 23:600. [PMID: 35054783 PMCID: PMC8776095 DOI: 10.3390/ijms23020600] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Of increasing prevalence, diabetes is characterised by elevated blood glucose and chronic inflammation that precedes the onset of multiple secondary complications, including those of the kidney and the eye. As the leading cause of end stage renal disease and blindness in the working population, more than ever is there a demand to develop clinical interventions which can both delay and prevent disease progression. Connexins are membrane bound proteins that can form pores (hemichannels) in the cell membrane. Gated by cellular stress and injury, they open under pathophysiological conditions and in doing so release 'danger signals' including adenosine triphosphate into the extracellular environment. Linked to sterile inflammation via activation of the nod-like receptor protein 3 inflammasome, targeting aberrant hemichannel activity and the release of these danger signals has met with favourable outcomes in multiple models of disease, including secondary complications of diabetes. In this review, we provide a comprehensive update on those studies which document a role for aberrant connexin hemichannel activity in the pathogenesis of both diabetic eye and kidney disease, ahead of evaluating the efficacy of blocking connexin-43 specific hemichannels in these target tissues on tissue health and function.
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Affiliation(s)
- Chelsy L. Cliff
- Joseph Banks Laboratories, School of Life, Sciences University of Lincoln, Lincoln LN6 7DL, UK; (C.L.C.); (B.M.W.); (P.E.S.)
| | - Bethany M. Williams
- Joseph Banks Laboratories, School of Life, Sciences University of Lincoln, Lincoln LN6 7DL, UK; (C.L.C.); (B.M.W.); (P.E.S.)
| | - Christos E. Chadjichristos
- National Institutes for Health and Medical Research, UMR-S1155, Batiment Recherche, Tenon Hospital, 4 Rue de la Chine, 75020 Paris, France;
| | - Ulrik Mouritzen
- Ciana Therapeutics, Ole Maaloes Vej 3, 2200 Copenhagen N, Denmark;
| | - Paul E. Squires
- Joseph Banks Laboratories, School of Life, Sciences University of Lincoln, Lincoln LN6 7DL, UK; (C.L.C.); (B.M.W.); (P.E.S.)
| | - Claire E. Hills
- Joseph Banks Laboratories, School of Life, Sciences University of Lincoln, Lincoln LN6 7DL, UK; (C.L.C.); (B.M.W.); (P.E.S.)
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Yang YY, Gao ZX, Mao ZH, Liu DW, Liu ZS, Wu P. Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy. Front Endocrinol (Lausanne) 2022; 13:1079465. [PMID: 36743936 PMCID: PMC9889542 DOI: 10.3389/fendo.2022.1079465] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/28/2022] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Accumulating evidence indicates that mitophagy is crucial for the development of diabetic nephropathy (DN). However, little is known about the key genes involved. The present study is to identify the potential mitophagy-related genes (MRGs) in DN. METHODS Five datasets were obtained from the Gene Expression Omnibus (GEO) database and were split into the training and validation set. Then the differentially expressed MRGs were screened and further analyzed for GO and KEGG enrichment. Next, three algorithms (SVM-RFE, LASSO and RF) were used to identify hub genes. The ROC curves were plotted based on the hub genes. We then used the CIBERSORT algorithm to assess the infiltration of 22 types of immune cells and explore the correlation between hub genes and immune cells. Finally, the Nephroseq V5 tool was used to analyze the correlation between hub genes and GFR in DN patients. RESULTS Compared with the tubulointerstitium, the expression of MRGs was more noticeably varied in the glomeruli. Twelve DE-MRGs were identified in glomerular samples, of which 11 genes were down-regulated and only MFN1 was up-regulated. GO and KEGG analysis indicated that several enrichment terms were associated with changes in autophagy. Three genes (MFN1, ULK1 and PARK2) were finally determined as potential hub genes by three algorithms. In the training set, the AUROC of MFN1, ULK1 and PARK2 were 0.839, 0.906 and 0.842. However, the results of the validation set demonstrated that MFN1 and PARK2 had no significant difference in distinguishing DN samples from healthy controls, while the AUROC of ULK1 was 0.894. Immune infiltration analysis using CIBERSORT showed that ULK1 was positively related to neutrophils, whereas negatively related to M1 and M2 macrophages. Finally, ULK1 was positively correlated with GFR in Nephroseq database. CONCLUSIONS ULK1 is a potential biomarker for DN and may influence the development of diabetic nephropathy by regulating mitophagy.
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Affiliation(s)
- Yuan-Yuan Yang
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhong-Xiuzi Gao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zi-Hui Mao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Dong-Wei Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhang-Suo Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
- *Correspondence: Peng Wu, ; Zhang-Suo Liu,
| | - Peng Wu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
- *Correspondence: Peng Wu, ; Zhang-Suo Liu,
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Liu J, Zhang Y, Sheng H, Liang C, Liu H, Moran Guerrero JA, Lu Z, Mao W, Dai Z, Liu X, Zhang L. Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus. Front Immunol 2021; 12:733808. [PMID: 34925317 PMCID: PMC8678409 DOI: 10.3389/fimmu.2021.733808] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/04/2021] [Indexed: 12/29/2022] Open
Abstract
Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.
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Affiliation(s)
- Jialing Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Yanmei Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongqin Sheng
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chunling Liang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | - Huazhen Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | | | - Zhaoyu Lu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Mao
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhenhua Dai
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Diseases, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xusheng Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
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Wang Y, Zhao M, Zhang Y. Identification of fibronectin 1 (FN1) and complement component 3 (C3) as immune infiltration-related biomarkers for diabetic nephropathy using integrated bioinformatic analysis. Bioengineered 2021; 12:5386-5401. [PMID: 34424825 PMCID: PMC8806822 DOI: 10.1080/21655979.2021.1960766] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Immune cell infiltration (ICI) plays a pivotal role in the development of diabetic nephropathy (DN). Evidence suggests that immune-related genes play an important role in the initiation of inflammation and the recruitment of immune cells. However, the underlying mechanisms and immune-related biomarkers in DN have not been elucidated. Therefore, this study aimed to explore immune-related biomarkers in DN and the underlying mechanisms using bioinformatic approaches. In this study, four DN glomerular datasets were downloaded, merged, and divided into training and test cohorts. First, we identified 55 differentially expressed immune-related genes; their biological functions were mainly enriched in leukocyte chemotaxis and neutrophil migration. The CIBERSORT algorithm was then used to evaluate the infiltrated immune cells; macrophages M1/M2, T cells CD8, and resting mast cells were strongly associated with DN. The ICI-related gene modules as well as 25 candidate hub genes were identified to construct a protein-protein interactive network and conduct molecular complex detection using the GOSemSim algorithm. Consequently, FN1, C3, and VEGFC were identified as immune-related biomarkers in DN, and a related transcription factor-miRNA-target network was constructed. Receiver operating characteristic curve analysis was estimated in the test cohort; FN1 and C3 had large area under the curve values (0.837 and 0.824, respectively). Clinical validation showed that FN1 and C3 were negatively related to the glomerular filtration rate in patients with DN. Six potential therapeutic small molecule compounds, such as calyculin, phenamil, and clofazimine, were discovered in the connectivity map. In conclusion, FN1 and C3 are immune-related biomarkers of DN.
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Affiliation(s)
- Yuejun Wang
- Department of Nephrology, Zhejiang Aged Care Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Mingming Zhao
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu Zhang
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Tao Y, Wei X, Yue Y, Wang J, Li J, Shen L, Lu G, He Y, Zhao S, Zhao F, Weng Z, Shen X, Zhou L. Extracellular vesicle-derived AEBP1 mRNA as a novel candidate biomarker for diabetic kidney disease. J Transl Med 2021; 19:326. [PMID: 34332599 PMCID: PMC8325821 DOI: 10.1186/s12967-021-03000-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 07/23/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND A novel and improved methodology is still required for the diagnosis of diabetic kidney disease (DKD). The aim of the present study was to identify novel biomarkers using extracellular vesicle (EV)-derived mRNA based on kidney tissue microarray data. METHODS Candidate genes were identified by intersecting the differentially expressed genes (DEGs) and eGFR-correlated genes using the GEO datasets GSE30528 and GSE96804, followed by clinical parameter correlation and diagnostic efficacy assessment. RESULTS Fifteen intersecting genes, including 8 positively correlated genes, B3GALT2, CDH10, MIR3916, NELL1, OCLM, PRKAR2B, TREM1 and USP46, and 7 negatively correlated genes, AEBP1, CDH6, HSD17B2, LUM, MS4A4A, PTN and RASSF9, were confirmed. The expression level assessment results revealed significantly increased levels of AEBP1 in DKD-derived EVs compared to those in T2DM and control EVs. Correlation analysis revealed that AEBP1 levels were positively correlated with Cr, 24-h urine protein and serum CYC and negatively correlated with eGFR and LDL, and good diagnostic efficacy for DKD was also found using AEBP1 levels to differentiate DKD patients from T2DM patients or controls. CONCLUSIONS Our results confirmed that the AEBP1 level from plasma EVs could differentiate DKD patients from T2DM patients and control subjects and was a good indication of the function of multiple critical clinical parameters. The AEBP1 level of EVs may serve as a novel and efficacious biomarker for DKD diagnosis.
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Affiliation(s)
- Yiying Tao
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Xing Wei
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Yue Yue
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Jiaxin Wang
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Jianzhong Li
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Lei Shen
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Guoyuan Lu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Yang He
- MOE Engineering Center of Hematological Disease, Soochow University, Suzhou, 215123, China
- National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- MOH Key Lab of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Shidi Zhao
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Fan Zhao
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Zhen Weng
- MOE Engineering Center of Hematological Disease, Soochow University, Suzhou, 215123, China
- Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, China
- National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Xiahong Shen
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
| | - Ling Zhou
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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Wan S, Wan S, Jiao X, Cao H, Gu Y, Yan L, Zheng Y, Niu P, Shao F. Advances in understanding the innate immune-associated diabetic kidney disease. FASEB J 2021; 35:e21367. [PMID: 33508160 DOI: 10.1096/fj.202002334r] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/16/2020] [Accepted: 12/28/2020] [Indexed: 12/26/2022]
Abstract
Millions of human deaths occur annually due to chronic kidney disease, caused by diabetic kidney disease (DKD). Despite having effective drugs controlling the hyperglycemia and high blood pressure, the incidence of DKD is increasing, which indicates the need for the development of novel therapies to control DKD. In this article, we discussed the recent advancements in the basic innate immune mechanisms in renal tissues triggered under the diabetes environment, leading to the pathogenesis and progression of DKD. We also summarized the currently available innate immune molecules-targeting therapies tested against DKD in clinical and preclinical settings, and highlighted additional drug targets that could potentially be employed for the treatment of DKD. The improved understanding of the disease pathogenesis may open avenues for the development of novel therapies to rein in DKD, which consequently, can reduce morbidity and mortality in humans in the future.
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Affiliation(s)
- Shengfeng Wan
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Shengkai Wan
- Department of Operations Management, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Xiaojing Jiao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Huixia Cao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Yue Gu
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Lei Yan
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Yan Zheng
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Peiyuan Niu
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
| | - Fengmin Shao
- Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, China
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Moratal C, Laurain A, Naïmi M, Florin T, Esnault V, Neels JG, Chevalier N, Chinetti G, Favre G. Regulation of Monocytes/Macrophages by the Renin-Angiotensin System in Diabetic Nephropathy: State of the Art and Results of a Pilot Study. Int J Mol Sci 2021; 22:ijms22116009. [PMID: 34199409 PMCID: PMC8199594 DOI: 10.3390/ijms22116009] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/17/2021] [Accepted: 05/28/2021] [Indexed: 12/24/2022] Open
Abstract
Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin-angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2.
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Affiliation(s)
- Claudine Moratal
- Université Côte d’Azur, INSERM, C3M, 06204 Nice, France;
- Correspondence:
| | - Audrey Laurain
- Faculty of Medicine, Côte d’Azur University, 06107 Nice, France; (A.L.); (V.E.); (G.F.)
- Centre National de la Recherche Scientifique, UMR 7073, Laboratory of Physiology and Molecular Medicine (LP2M), 06107 Nice, France
- Nephrology, Dialysis and Transplantation Department, University Hospital, 06002 Nice, France;
| | - Mourad Naïmi
- Université Côte d’Azur, CHU, 06000 Nice, France;
| | - Thibault Florin
- Nephrology, Dialysis and Transplantation Department, University Hospital, 06002 Nice, France;
| | - Vincent Esnault
- Faculty of Medicine, Côte d’Azur University, 06107 Nice, France; (A.L.); (V.E.); (G.F.)
- Nephrology, Dialysis and Transplantation Department, University Hospital, 06002 Nice, France;
| | - Jaap G. Neels
- Université Côte d’Azur, INSERM, C3M, 06204 Nice, France;
| | - Nicolas Chevalier
- Université Côte d’Azur, CHU, INSERM, C3M, 06000 Nice, France; (N.C.); (G.C.)
| | - Giulia Chinetti
- Université Côte d’Azur, CHU, INSERM, C3M, 06000 Nice, France; (N.C.); (G.C.)
| | - Guillaume Favre
- Faculty of Medicine, Côte d’Azur University, 06107 Nice, France; (A.L.); (V.E.); (G.F.)
- Centre National de la Recherche Scientifique, UMR 7073, Laboratory of Physiology and Molecular Medicine (LP2M), 06107 Nice, France
- Nephrology, Dialysis and Transplantation Department, University Hospital, 06002 Nice, France;
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Chen XJ, Zhang H, Yang F, Liu Y, Chen G. DNA Methylation Sustains "Inflamed" Memory of Peripheral Immune Cells Aggravating Kidney Inflammatory Response in Chronic Kidney Disease. Front Physiol 2021; 12:637480. [PMID: 33737884 PMCID: PMC7962671 DOI: 10.3389/fphys.2021.637480] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/04/2021] [Indexed: 01/19/2023] Open
Abstract
The incidence of chronic kidney disease (CKD) has rapidly increased in the past decades. A progressive loss of kidney function characterizes a part of CKD even with intensive supportive treatment. Irrespective of its etiology, CKD progression is generally accompanied with the development of chronic kidney inflammation that is pathologically featured by the low-grade but chronic activation of recruited immune cells. Cumulative evidence support that aberrant DNA methylation pattern of diverse peripheral immune cells, including T cells and monocytes, is closely associated with CKD development in many chronic disease settings. The change of DNA methylation profile can sustain for a long time and affect the future genes expression in the circulating immune cells even after they migrate from the circulation into the involved kidney. It is of clinical interest to reveal the underlying mechanism of how altered DNA methylation regulates the intensity and the time length of the inflammatory response in the recruited effector cells. We and others recently demonstrated that altered DNA methylation occurs in peripheral immune cells and profoundly contributes to CKD development in systemic chronic diseases, such as diabetes and hypertension. This review will summarize the current findings about the influence of aberrant DNA methylation on circulating immune cells and how it potentially determines the outcome of CKD.
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Affiliation(s)
- Xiao-Jun Chen
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Hong Zhang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fei Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Yu Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Guochun Chen
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
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Gajeton J, Krukovets I, Yendamuri R, Verbovetskiy D, Vasanji A, Sul L, Stenina‐Adognravi O. miR-467 regulates inflammation and blood insulin and glucose. J Cell Mol Med 2021; 25:2549-2562. [PMID: 33566451 PMCID: PMC7933977 DOI: 10.1111/jcmm.16224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 09/24/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.
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Affiliation(s)
- Jasmine Gajeton
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
| | - Irene Krukovets
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | - Revanth Yendamuri
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Northeast Ohio Medical UniversityRootstownOHUSA
| | - Dmitriy Verbovetskiy
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | | | - Lidiya Sul
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Ohio University Heritage College of Osteopathic MedicineAthensOHUSA
| | - Olga Stenina‐Adognravi
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
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TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy. Inflamm Res 2020; 69:1215-1234. [PMID: 33044562 PMCID: PMC7658079 DOI: 10.1007/s00011-020-01411-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 09/09/2020] [Accepted: 10/03/2020] [Indexed: 12/13/2022] Open
Abstract
Objective and design Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN. Methods TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) and lentiviral vector-mediated TAB1 knockdown was used in streptozotocin (STZ)-induced diabetic mice. Western blotting, flow cytometry, qRT-PCR, ELISA, PAS staining and immunohistochemical staining were used for assessment of TAB1/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy. Results We found that TAB1/NF-κB/HIF-1α, iNOS and glycolysis were up-regulated in BMMs under HG conditions, leading to release of further inflammatory factors, Downregulation of TAB1 could inhibit glycolysis/polarization of macrophages and inflammation in vivo and in vitro. Furthermore, albuminuria, the tubulointerstitial damage index and glomerular mesangial expansion index of STZ-induced diabetic nephropathy mice were decreased by TAB1 knockdown. Conclusions Our results suggest that the TAB1/NF-κB/HIF-1α signaling pathway regulates glycolysis and activation of macrophages in DN. Electronic supplementary material The online version of this article (10.1007/s00011-020-01411-4) contains supplementary material, which is available to authorized users.
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Klimontov VV, Korbut AI, Orlov NB, Dashkin MV, Konenkov VI. Multiplex Bead Array Assay of a Panel of Circulating Cytokines and Growth Factors in Patients with Albuminuric and Non-AlbuminuricDiabetic Kidney Disease. J Clin Med 2020; 9:3006. [PMID: 32961903 PMCID: PMC7565054 DOI: 10.3390/jcm9093006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
A panel of cytokines and growth factors, mediating low-grade inflammation and fibrosis, was assessed in patients with type 2 diabetes (T2D) and different patterns of chronic kidney disease (CKD). Patients with long-term T2D (N = 130) were classified into four groups: no signs of CKD; estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 without albuminuria; albuminuria and eGFR ≥60 mL/min/1.73 m2; albuminuria and eGFR <60 mL/min/1.73 m2. Thirty healthy subjects were acted as control. Twenty-seven cytokines and growth factors were assessed in serum by multiplex bead array assay. Serum hs-CRP, urinary nephrin, podocine, and WFDC2 were measured by ELISA. Patients with T2D showed elevated IL-1Ra, IL-6, IL-17A, G-CSF, IP-10, MIP-1α, and bFGF levels; concentrations of IL-4, IL-12, IL-15, INF-γ, and VEGF were decreased. IL-6, IL-17A, G-CSF, MIP-1α, and bFGF correlated negatively with eGFR; IL-10 and VEGF demonstrated negative associations with WFDC2; no relationships with podocyte markers were found. Adjusted IL-17A and MIP-1α were predictors of non-albuminuric CKD, IL-13 predicted albuminuria with preserved renal function, meanwhile, IL-6 and hsCRP were predictors of albuminuria with eGFR decline. Therefore, albuminuric and non-albuminuric CKD in T2D patients are associated with different pro-inflammatory shifts in the panel of circulating cytokines.
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Affiliation(s)
- Vadim V. Klimontov
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630060 Novosibirsk, Russia; (A.I.K.); (N.B.O.); (M.V.D.); (V.I.K.)
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Liao H, Li Y, Zhang X, Zhao X, Zheng D, Shen D, Li R. Protective Effects of Thalidomide on High-Glucose-Induced Podocyte Injury through In Vitro Modulation of Macrophage M1/M2 Differentiation. J Immunol Res 2020; 2020:8263598. [PMID: 32908940 PMCID: PMC7474395 DOI: 10.1155/2020/8263598] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/25/2020] [Accepted: 07/11/2020] [Indexed: 12/19/2022] Open
Abstract
Objective. It has been shown that podocyte injury represents an important pathological basis that contributes to proteinuria and eventually leads to kidney failure. High glucose (HG) activates macrophage polarization, further exacerbating HG-induced podocyte injury. Our previous study on diabetic nephropathy rats indicated that thalidomide (Tha) has renoprotective properties. The present study explored the effects of Tha on mRNA and protein expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor- (TNF-) α, mannose receptor (CD206), and arginase- (Arg-) 1 in HG-activated macrophages. iNOS and TNF-α are established as markers of classically activated macrophage (M1). CD206 and Arg-1 are regarded as markers of alternatively activated macrophages (M2). During the experiment, the supernatants of (HG)-treated and (Tha)-treated macrophages, designated as (HG) MS and (Tha) MS, were simultaneously collected and processed. TNF-α and interleukin- (IL-) 1β levels as well as protein expressions of nephrin and podocin in HG, (HG) MS, and (Tha) MS-cultured podocytes were evaluated. The results showed that compared to the 11.1 mM normal glucose (NG), the 33.3 mM HG-cultured RAW 264.7 cells exhibited upregulated iNOS and TNF-α mRNAs and protein expressions, and downregulated CD206 and Arg-1 expressions significantly (p < 0.05). Tha 200 μg/ml suppressed iNOS and TNF-α, and promoted CD206 and Arg-1 expressions significantly compared to the HG group (p < 0.05). Furthermore, (HG) MS-treated podocytes showed an increase in TNF-α and IL-1β levels and a downregulation in nephrin and podocin expression significantly compared to NG-treated and HG-treated podocytes (p < 0.05). The (Tha 200 μg/ml) MS group exhibited a decrease in TNF-α and IL-1β level, and an upregulation in nephrin and podocin expressions significantly compared to the (HG) MS group (p < 0.05). Our research confirmed that HG-activated macrophage differentiation aggravates HG-induced podocyte injury in vitro and the protective effects of Tha might be related to its actions on TNF-α and IL-1β levels via its modulation on M1/M2 differentiation.
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Affiliation(s)
- Hui Liao
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Yuanping Li
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Xilan Zhang
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Xiaoyun Zhao
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Dan Zheng
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Dayue Shen
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Rongshan Li
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
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Fan L, Gao W, Nguyen BV, Jefferson JR, Liu Y, Fan F, Roman RJ. Impaired renal hemodynamics and glomerular hyperfiltration contribute to hypertension-induced renal injury. Am J Physiol Renal Physiol 2020; 319:F624-F635. [PMID: 32830539 DOI: 10.1152/ajprenal.00239.2020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1BN congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1BN Add3KO (Add3KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in Add3KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus Add3KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in Add3KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in Add3KO rats. The degree of renal injury was greater in Add3KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in Add3KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive Add3KO rats.
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Affiliation(s)
- Letao Fan
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Wenjun Gao
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Bond V Nguyen
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Joshua R Jefferson
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Yedan Liu
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Fan Fan
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Richard J Roman
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
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Macrophage Phenotype and Fibrosis in Diabetic Nephropathy. Int J Mol Sci 2020; 21:ijms21082806. [PMID: 32316547 PMCID: PMC7215738 DOI: 10.3390/ijms21082806] [Citation(s) in RCA: 160] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/11/2020] [Accepted: 04/14/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN.
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