Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor

Advanced glycation endproducts ( AGEs) and a receptor for AGEs ( RAGE) have been linked in the pathogenesis of diabetic nephropathy. RAGE is usually localized to podocytes and is increased in diabetes. RAGE activation increases reactive oxygen species production, which mediates hyperglycemia-induced podocyte apoptosis in early diabetic nephropathy. Here, we examined the interaction of AGE and RAGE on podocyte apoptosis. When we exposed murine cultured podocytes to bovine serum albumin ( BSA) that was modified by AGEs or to carboxymethyl-lysine BSA, more apoptosis was found when compared with unmodified BSA. Similarly, more podocytes underwent detachment and apoptosis when cultured on AGE-modified collagen IV than on native collagen IV. AGEs isolated from sera of patients with chronic kidney disease also caused apoptosis of podocytes. Apoptosis was diminished by small interference RNA ( siRNA) for RAGE in podocytes exposed to AGE-BSA, but not to AGE-modified collagen IV. Both AGE- and carboxymethyl-lysine modified-BSA activated p38MAP kinase and inhibition of this kinase reduced the apoptotic effect of AGE-BSA. Exposure to AGE-BSA was associated with Akt dephosphorylation and FOXO4 transcriptional activation leading to an increase in the expression of an effector protein of apoptosis, Bim. siRNA for FOXO4 abolished AGE-BSA-induced apoptosis of podocytes. Our study suggests that an AGE-RAGE interaction contributes to podocyte apoptosis by activation of the FOXO4 transcription factor.