摘要：

This review deals with the effect of hypoglycemia and oxidative stress on renal tissue in diabetes. It focuses on the effect of advanced glycation endproducts (AGEs). It covers the potential utility of this pathway as a future therapeutic target for prevention and management of diabetic nephropathy. INTRODUCTION AGEs, generated in hyperglycemic conditions, by non enzymatic glycation, protein oxidation and lipid oxidation, including pentosidine, carboxymethyl lysine AGEs, and pyrallines, are well known to cause diabetic complications. (1, 2) AGEs can be measured in tissue as well as serum or plasma, and rise in parallel with hyperglycemia (because of increased formation), and decline in renal function (due to reduction in renal clearance). AGEs react with various receptors including scavenger receptors including scavenger receptor type A, CD 36, galectin-3, and RAGE. RAGE is a member of the immunoglobulin superfamily of cell-surface molecules, and activities intracellular signal transduction pathways to achieve the effects of AGE. RAGE is expressed to a greater degree in diabetic kidneys, at the glomerular visceral epithelial cell (podocyte). (3) RAGE is a receptor for other ligands such as 5100/calgranulins (100), amphoterin [high-mobility group box-1 (HMGB 1) protein], amyloid-β peptide, β-sheet fibrils and Mac-1, all of which are pro-inflammatory molecules. BLOCKADE OF RAGE Soluble RAGE (RAGE), or neutralizing antibody to RAGE have been used to block the ligand-RAGE axis, in animal experiments. Blockade is also simulated in mouse mesangial cells producing limited RAGE-specific ribozymes. (1) In these models, improvements in kidney morphology and biochemical parameters have been noted with RAGE antagonism. These animal experiments emphasize the importance of gluco oxidation via the RAGE axis in the pathogenesis of diabetic nephropathy. Genetic models have also been studied to explore the role of RAGE. While transgenic mice with other expression of RAGE demonstrate increased nephromegaly, glomerular hypertrophy, mesangial expansion, advanced glomerulosclerosis, increased albuminuria and serum creatinine than RAGE transgene-negative mice. Administration of OPB-9195, an AGE inhibitor, was able to prevent nephropathy in these mice (3). Similar studies have also demonstrated increased kidney/body weight ratio, and increased renal cortex expression of VEGF antigen and TGF-β transcription, in RAGE-expressing mice with diabetes, as compared to RAGE-null mice. (4) DOWNSTREAM EFFECTS OF RAGE SIGNALING RAGE activation leads to a large number of diverse signaling pathways, which vary according to cell type and duration of stimulation. RAGE signaling triggers recruitment of p 21 ras, erk 12 (p44/p42) MAP kinases, p38 and SAPK/JNK MAP kinases, rho GTPases, phosphoinositol-3 kinase, and the JAK/STAT pathway, while activating transcription factors such as nuclear factor-kB and CREB (1). RAGE signalling is linked to TGF-β-Smad signalling and to angiotensin II. The angiotensin receptor blocker, candesartan, is able to reduce AGE-induced phosphorylation of Smad 2 and TGF-β inducible promotor activity. (5) Gluco oxidative stress in the diabetic kidney 2 of 3 RAGE activation also leads to p21 waf expression, collagen production, and epithelial-myofibroblast transdifferentiation, which may explain a potential role for RAGE in the progression of tubulo interstitial disease. (7, 8) THERAPEUTIC IMPLICATIONS AGE and RAGE both have been used as therapeutic targets for prevention of diabetic nephropathy. The AGE inhibitor aminoguanidine (pimagedine) has been used in human subjects with type 1 diabetes. (9) Though the drug increased the time taken to double serum creatinine, reduced the rate of decline of glomerular filtration rate, and reduced 24 hour proteinuria, three subjects developed glomerulonephritis. Agents such as ALT-711, an AGE cross link breakers, have been assessed in animal models of diabetes nephropathy, and in elderly humans with vascular stiffening. Antagonists such as pyridoxamine and LR-90 have been studied in animals. (1) While

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