The prevalence of diabetic nephropathy has increased dramatically and is now the first cause of end-stage renal disease requiring renal replacement therapy worldwide (72). Although the genetic background is important in determining susceptibility to diabetic nephropathy, exposure to chronic hyperglycemia leading to the subsequent activation of multiple pathogenic pathways appears to be the main initiating factor (2,3,4-6,41).
Diabetic nephropathy occurs in up to 30%-40% of diabetic patients. The initial abnormalities include glomerular hyperfiltration and hyperperfusion resulting in microalbu-minuria, increased glomerular basement membrane thickening, and mesangial ECM deposition. These processes are followed by mesangial hypertrophy, diffuse and nodular glomerulosclerosis, tubulointerstitial fibrosis, and eventually progressive renal failure (73).
The ability to culture cells that are affected by AGEs has provided an important insight into the mechanisms of action of these adducts, their receptors and the way they may contribute to tissue dysfunction in diabetes. In vitro, AGEs bind to renal mesangial cells through AGE receptors, which initiate overproduction of matrix proteins and changes in the expression of matrix metalloproteinases and proteinase inhibitors (74,75). Exposure of rat mesangial cells to AGE-rich proteins results in mesangial oxidative stress and activation of RAGE or other processes, e.g., protein kinase C-P (76) or angiotensin II causing, for instance, in vitro inhibition of nephrin gene expression (77) or induction of apoptosis and secretion of vascular endothelin growth factor (VEGF) and monocyte chemotactic peptide-1 proteins, events that were prevented by ^-acetylcysteine (78). AGEs also stimulate production of collagen IV and fibronectin in glomerular endothelial cells (79).
Immunohistochemical studies of kidneys from normal and diabetic rats show that glomerular basement membrane, mesangium, podocytes, and renal tubular cells accumulate high levels of AGEs with AGE concentrations rising with age and more rapidly with diabetes (80,81). Moreover, the intensity of CML immunostaining is greatest in the areas of extensive glomerular sclerosis characteristic of advanced diabetic nephropathy (82).
Short-term exogenous AGE administration to normal, nondiabetic animals has reproduced some of the vascular defects associated with clinical diabetic nephropathy including induction of basement membrane components (e.g., a1-collagen IV) or transforming growth factor (TGF)-P (82,83). Furthermore, chronic treatment of animals with AGE albumin can reproduce glomerular hypertrophy, basement membrane thickening, extracellular mesangial matrix expansion and albuminuria, all consistent with findings of diabetic nephropathy (82,83).
The role of AGEs in the pathogenesis of diabetic nephropathy has been supported by studies in transgenic animals. RAGE overexpression in diabetic mice resulted in increased albuminuria, elevated serum creatinine, renal hypertrophy, mesangial expansion, and glomerulosclerosis (60), although blockade of RAGE by soluble truncated RAGE suppressed structural and functional components associated with nephropathy in db/db mice (58).
AGE inhibitors have been shown to prevent AGE accumulation in renal structures and diabetic nephropathy in diabetic animal models (84-87). Aminoguanidine ameliorated overexpression of a1-type IV collagen, laminin B1, TGF-P, and platelet-derived growth factor, all associated with glomerular hypertrophy (87). ORB-9195 administration to diabetic rats resulted in a reduction in the progression of diabetic nephropathy by blocking type IV collagen and overproduction of TGF-P and VEGF (88). In the same context, the AGE-breaker, ALT-711, has also been shown to afford renoprotection to diabetic animals (89).
Biopsy samples from kidneys from diabetic subjects have demonstrated increased AGE deposition at AGE-specific binding sites throughout the renal cortex (90,91). Specific AGE compounds (e.g., CML, pyralline, and pentosidine) have been identified in renal tissue of diabetics with or without end-stage renal disease; AGE accumulation appeared to parallel the severity of diabetic nephropathy (92). Also, whereas low-level RAGE expression in normal control human subjects was restricted to podocytes, glom-eruli of patients with diabetic nephropathy demonstrated diffuse upregulation of RAGE expression in podocytes, colocalizing with synaptopodin expression (93). A recent study in kidney biopsies from patients with diabetic nephropathy showed significant reduction of nephrin, an important regulator of the glomerular filter integrity. In the same study, cultured podocytes showed significant downregulation in nephrin expression when glycated albumin was added (77).
In a clinical study of type 1 diabetic patients serum levels of AGEs increased significantly as patients progressed from normal to microalbuminuria, clinical nephropathy and hemodialysis and correlated positively with urinary albumin excretion (94).
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