Matrix metalloproteinase-9 deficiency attenuates diabetic nephropathy by modulation of podocyte functions and dedifferentiation

Li, Szu Yuan; Huang, Po Hsun; Yang, An Hang; Tarng, Der Cherng; Wu, Yang Chang; Lin, Chih Ching; Chen, Jaw Wen; Schmid‐Schönbein, Geert W.; Lin, Shing Jong

doi:10.1038/ki.2014.67

Cited by 109 publications

(89 citation statements)

References 59 publications

(62 reference statements)

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“…50 The primary antibodies used were: anti-active b-catenin (NonPhospho b-catenin, D13A1; Cell Signaling Technology), anti-nephrin (Acris, Herford, Germany), anti-snail, anti-VEGF, anti-TGF-b (Abcam, Inc., Cambridge, UK), and anti-FHL2 (MBL Life Science, Nagoya, Japan).…”

Section: Western Blot Analysismentioning

confidence: 99%

Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease

Huang

Tarng

et al. 2015

Journal of the American Society of Nephrology

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Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/b-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-b1, activated FHL2 protein and Wnt/b-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/b-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2 +/+ mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2 +/+ mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactions with b-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/b-catenin-induced podocytopathy. 26: 3072-3084, 201526: 3072-3084, . doi: 10.1681 Diabetic kidney disease (DKD) is the leading cause of ESRD, affecting 10%-40% of diabetic patients, and the cost of RRT remains a large economic burden for the health care system. Proteinuria is a major and primary clinical aspect of DKD and causes tubulointerstitial lesions that lead to renal dysfunction. 1 Reducing proteinuria may therefore be a principal therapeutic target to improve renal outcome in patients with DKD. However, the pathophysiologic mechanism of DKD is multifactorial, and some patients develop treatment-resistant proteinuria that results in ESRD despite intensive BP and glycemia control. Thus, identification of major DKD mechanisms and development of new therapeutic options are needed. Glomerular epithelial cells, also called podocytes, are predominantly responsible for maintaining the glomerular filtration barrier. Podocytes are highly specialized, terminally differentiated cells that cannot proliferate. 2 Recently, hyperactive podocyte J Am Soc Nephrol

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Section: Western Blot Analysismentioning

confidence: 99%

Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease

Huang

Tarng

et al. 2015

Journal of the American Society of Nephrology

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“…Indeed, up-regulation of MMP-9 expression can be found in several glomerular diseases accompanied by proteinuria, including membranous nephropathy in humans [McMillan et al, 1996] or diabetic nephropathy in the mouse. Increased plasma or urinary MMP-9 precedes albuminuria in diabetic patients and MMP-9 deficiency limits diabetic kidney injury in the mouse [Ebihara et al, 1998;Li et al, 2014]. Comparative analysis of MMP-9 expression and proteinuria progression in membranous nephropathy suggests a direct involvement of MMP-9 in the alteration of the permeability of the filtration barrier [McMillan et al, 1996].…”

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confidence: 99%

CD154 Induces Matrix Metalloproteinase‐9 Secretion in Human Podocytes

Rigothier

Daculsi

Lepreux

et al. 2016

J of Cellular Biochemistry

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Matrix remodeling is a key feature of glomerulosclerosis secondary to diabetes or hypertension. Podocytes contribute to glomerular basement membrane (GBM) turnover by producing matrix components and matrix remodelling enzymes, including matrix metalloproteinases (MMPs). The CD40/CD154 signaling pathway modulates matrix remodeling through the synthesis of MMPs and tissue inhibitors of MMPs. Platelets are a primary blood reservoir of CD154. Here we studied, the impact of the CD154/CD40 pathway on MMP-9 expression by cultured human podocytes. The role of CD40/CD154 was evaluated upon exposure of podocytes to recombinant human CD154 (rhCD154) or activated platelet supernatants from healthy human subjects. We first showed by protein and mRNA expression that CD40 was synthesized by podocytes and detectable on kidney tissue sections. CD40 expression was acquired during podocyte differentiation and enhanced upon exposure to rhCD154. In podocytes, rhCD154 induced an increase of MMP-9 production as shown by RT-PCR, Western blot and and gelatin zymography. Activated platelet supernatants induced MMP-9 mRNA synthesis in podocytes, an effect reduced by anti-CD40 antibody. Our results underscore a potential role for platelets through the CD40/CD154 signaling pathway in the control of GBM synthesis and degradation, via its regulatory role on MMP-9 production. CD154 secretion by activated platelets may contribute to GBM alterations in proteinuric nephropathies. J. Cell. Biochem. 117: 2737-2747, 2016. © 2016 Wiley Periodicals, Inc.

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“…In DN patients, the expression of MMP-9 protein and its catalytic activity increased. However, DN can be assuaged through the suppression of the expression of MMP-9 in kidneys via genetic effects or drug intervention [12]. All these results suggest that MMP-9 may be involved in the occurrence and development of DN.…”

Section: Discussionmentioning

confidence: 99%

Badanie zależności między metylacją regionu promotora genu MMP-9 a nefropatią cukrzycową

Yang¹,

Feng²,

Yu³

et al. 2018

Endokrynologia Polska

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Introduction: This study aims to explore the relationship between the methylation of matrix metalloproteinase (MMP)-9 gene promoter region and diabetic nephropathy (DN) through the detection of the methylation level of MMP-9 gene promoter region in the peripheral blood of patients with DN in different periods and serum MMP-9 concentration. Material and methods: The methylation level of the MMP-9 gene promoter region was detected by methylation-specific polymerase chain reaction (MSP), and the content of MMP-9 in serum was determined by enzyme-linked immunosorbent assay (ELISA). Results: Results of the statistical analysis revealed that serum MMP-9 protein expression levels gradually increased in patients in the simple diabetic group, early diabetic nephropathy group, and clinical diabetic nephropathy group, compared with the control group, and the difference was statistically significant (P < 0.05). Compared with the control group, the methylation levels of MMP-9 gene promoter regions gradually decreased in patients in the simple diabetic group, early diabetic nephropathy group, and clinical diabetic nephropathy group, and the difference was statistically significant (P < 0.05). Furthermore, correlation analysis results indicated that the demethylation levels of the MMP-9 gene promoter region were positively correlated with serum protein levels, urinary albumin-to-creatinine ratio (UACR), urea, and creatinine, and was negatively correlated with GFR. Conclusions:The demethylation of the MMP-9 gene promoter region may be involved in the occurrence and development of diabetic nephropathy by regulating the expression of MMP-9 protein in serum. (Endokrynol Pol 2018; 69 (3): 269-275)

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Matrix metalloproteinase-9 deficiency attenuates diabetic nephropathy by modulation of podocyte functions and dedifferentiation

Cited by 109 publications

References 59 publications

Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease

Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease

CD154 Induces Matrix Metalloproteinase‐9 Secretion in Human Podocytes

Badanie zależności między metylacją regionu promotora genu MMP-9 a nefropatią cukrzycową

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