Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy.
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. One of the key mechanisms implicated in the pathogenesis of DN is non-enzymatic glycation (NEG). NEG is the irreversible attachment of reducing sugars onto free amino groups of proteins by a series of events, which include the formation of Schiff's base and an Amadori product to yield advanced glycation end products (AGEs). AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. AGEs activate several intracellular signaling cascades upon interaction with receptor for AGEs (RAGE), which manifest in aberrant cellular responses such as inflammation, apoptosis and autophagy, whereas other receptors such as AGE-R1, AGE-R3 and scavenger receptors also bind to AGEs and ensue endocytosis and degradation of AGEs. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. Increased evidence supports that attenuation of AGE formation and/or inhibition of RAGE activation manifest(s) in improving renal function. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Therapies designed to target AGEs, such as inhibitors of AGEs formation and crosslink breakers, are discussed.
Anil
A
Kumar Pasupulati
P Swathi
PS
Chitra
G Bhanuprakash
GB
Reddy
D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D012084:Renin-Angiotensin System; D015398:Signal Transduction
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products