Matrix metalloproteinases: their potential role in the pathogenesis of diabetic nephropathy

Abstract

Matrix metalloproteinases (MMPs), a family of proteinases including collagenases, gelatinases, stromely-sins, matrilysins, and membrane-type MMPs, affect the breakdown and turnover of extracellular matrix (ECM).Moreover, they are major physiologic determinants of ECM degradation and turnover in the glomerulus. Renal hypertrophy and abnormal ECM deposition are hallmarks of diabetic nephropathy (DN), suggesting that altered MMP expression or activation contributes to renal injury in DN. Herein, we review and summarize recent information supporting a role for MMPs in the pathogenesis of DN. Specifically, studies describing dysregulated activity of MMPs and/or their tissue inhibitors in various experimental models of diabetes, including animal models of type 1 or type 2 diabetes, clinical investigations of human type 1 or type 2 diabetes, and kidney cell culture studies are reviewed. KeywordsGelatinase; Podocyte; Extracellular matrix; Proteinases; Proteinuria Diabetic nephropathy-general overviewDiabetic nephropathy is stated to be the most common cause of end-stage renal disease in the United States [1]. Between 20% and 30% of patients with type 1 diabetes mellitus (DM) or type 2 DM will develop nephropathy [1], and among patients with type 1 DM, diabetic nephropathy develops in 40-50% of patients with a 20-year history of disease [2]. Among those individuals who develop renal dysfunction, several risk factors for the development of renal disease have been identified, including duration of diabetes, age at diagnosis, race, systemic or glomerular hypertension, poor glycemic control, genetic predisposition to kidney disease, and dietary composition [1][2][3]. However, the precise pathogenic mechanisms involved in the initiation and progression of diabetic nephropathy remain incompletely understood.The development of diabetic nephropathy has been described as a five-stage process, progressing from glomerular hyperfiltration and nephromegaly (Stage 1), to glomerular basement membrane thickening and mesangial expansion (Stage 2), to microalbuminuria and eventual decline in glomerular filtration rate (Stage 3), to frank proteinuria with severe hypertension and sequelae of moderate to severe renal insufficiency (Stage 4), to eventual endstage renal disease (Stage 5) [4,5]. It has been hypothesized that the early changes in glomerular basement membrane thickness and content ultimately affect filtration properties of the © Humana Press Inc. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript glomerular basement membrane, leading first to increased urinary albumin excretion and eventually to proteinuria. Similar histological findings are also seen in many rodent models of diabetic nephropathy. Because enlargement of the kidney mesangium due to extracellular matrix over-accumulation is a major characteristic of diabetic nephropathy, and because MMPs produced by the mesangial cell account for up to 70% of extracellular matrix degradation and turnover in the kidney during normal matrix remodeling,...

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“…In humans the role of MMP-2 was confirmed in pathogenesis of tubulointerstitial fibrosis in diabetic nephropathy [11].…”

“…It has been documented that the gelatinase family of MMPs (MMP-2, MMP-9) plays the crucial role in fibrosis and chronic kidney disease progression [6,11]. MMP-2 is normally expressed in mesangial cells and podocytes during inflammation states.…”

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“…MMPs play essential roles in many aspects of biology, including cell proliferation, differentiation, apoptosis, and migration. These processing enzymes have clear links to cancer and tumor progression, in which proteolysis of the ECM is required to accommodate increased growth, migration, and invasion of tumor cells (Korpos et al, 2009;Thrailkill et al, 2009;Tonti et al, 2009).…”

Drugs for Diabetic Nephropathy- Full Review

“…The mechanism remains unclear. [189] [190][191][192][193][194][195][196] MMP-plays important role in development of diabetic nephropathy. [193,194] Dysregulation in NGAL, MMP-9 aand MMP2 is noted in type1 diabetes.…”

“…[193,194] Dysregulation in NGAL, MMP-9 aand MMP2 is noted in type1 diabetes. [195,196] MMP9 MMP2 -can be biomarkers for early kidney damage.…”