Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy

Abstract

Diabetic late complications are characterized by morphological and biochemical alterations of the extracellular matrix. In particular, longstanding diabetes causes quantitative and qualitative changes in basement membrane structure of retinal and renal capilleries. Immunohistochemical investigations of diabetic kidneys with diffuse glomerulosclerosis show increased collagen type IV deposition in the mesangial matrix and decreased heparan sulfate proteoglycan content in the mesangial matrix and glomerular basement membrane as well. In nodular glomerulosclerosis normal basement membrane components are decreased or absent while the occurrence of collagen type III in this stage has been interpreted as an irreversible alteration of the glomerular structure. These changes seem to be the underlying cause for the alterations in renal functions like persistent albuminuria and proteinuria. Increased intra-and extracellular levels of glucose and its derivatives are thought to be responsible for diabetic tissue dysfunction although there are reports on possible genetic defects causing increased susceptibility to develop diabetic nephropathy. Recent results, however, focuse on the role of glucose-induced cytokine secretion as mediator for altered metabolism of glomerular matrix proteins. In vitro studies with cultured kidney cells have shown that the glucoseinduced dysregulation of the basement membrane synthesis may be mediated by a glucose dependent activation of protein kinase C. Alternatively or synergistically, the formation of AGE products formed after prolonged exposure of matrix proteins to elevated glucose may also lead to cytokine secretion subsequently inducing synthesis of cxtracellular matrix proteins. Studies in experimental animals confirm the diabetes induced dysregulation of the synthesis of extracellular matrix components on the molecular level.Abbreviations: HSPG=heparan sulfate proteoglycan; GBM= glomerular basement membrane; ECM=extracellular matrix; AGE = advanced glucosylation end products; TNF = tumor necrosis factor; bFGF=basic fibroblast growth factor

Differential Effects of Diabetes and Glomerulonephritis on Glomerular Basement Membrane Composition

“…The association between glomerular sclerosis and proteinuria suggests that altered ECM composition may contribute to the loss of permselectivity (7,9,14). Alternatively, the glomerular events that ultimately result in proteinuria and loss of GFR may also initiate sclerosis as an independent but concurrent event.…”

Increased atherosclerosis in streptozotocin-induced diabetic mice.

“…For instance, hyperglycemia increases diacylglycerol levels and activates protein kinase C activity in the aorta of streptozotocin (STZ) 1 -induced diabetic rats (5) and dogs (6). Thickening of the basement membranes in renal glomeruli and peripheral capillaries has been observed in STZ-induced diabetic rats (7) and diabetic patients (4). Hyperlipidemia is a feature of drug-induced diabetes in rats (8) and rabbits (9, 10), as well as poorly controlled diabetes in humans (11).…”

Thrombin down‐regulates the TGF‐β‐mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCR‐dependent activation of PAR‐1

“…Recent in vitro data have indicated that thrombin, through the activation of PAR-1, contributes to the pathology of acute renal injury and that APC plays a renoprotective role, possibly in part through the activation of the same receptor on kidney cells (Xu et al, 1995; Gupta et al, 2007, 2009; Isermann et al, 2007). These studies have used primary or immortalized proximal tubule epithelial (HK-2) cells as in vitro models to conclude that thrombin can initiate proinflammatory responses in the kidney through the stimulation of TGF-β and subsequent induction of ECM proteins (MacKay et al, 1989; Olgemoller and Schleicher, 1993; Ryan et al, 1994; Laping et al, 1997; Grandaliano et al, 2000; Shirato et al, 2003; Vesey et al, 2005; Du et al, 2010). The accumulation of ECM molecules is one common pathological feature of glomerular and tubular diseases observed in end-stage renal failure caused by severe sepsis and diabetic nephropathy (Wan et al, 2003; Bonventre and Zuk, 2004; Molitoris and Sutton, 2004).…”