Angiotensin‐converting enzyme inhibitors attenuated advanced glycation end products‐induced renal tubular hypertrophy via enhancing nitric oxide signaling

Advanced glycation end products (AGE) and angiotensin II were closely correlated with the progression of diabetic nephopathy (DN). Nitric oxide (NO) is a protective mediator of renal tubular hypertrophy in DN. Here, we examined the molecular mechanisms of angiotensin‐converting enzyme inhibitor (ACEI) and NO signaling responsible for diminishing AGE‐induced renal tubular hypertrophy. In human renal proximal tubular cells, AGE decreased NO production, inducible NOS activity, guanosine 3′,5′‐cyclic monophosphate (cGMP) synthesis, and cGMP‐dependent protein kinase (PKG) activation. All theses effects of AGE were reversed by treatment with ACEIs (captopril and enalapril), the NO donor S‐nitroso‐N‐acetylpenicillamine (SNAP), and the PKG activator 8‐para‐chlorophenylthio‐cGMPs (8‐pCPT‐cGMPs). In addition, AGE‐enhanced activation of extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK), and p38 mitogen‐activated protein kinase (MAPK) were clearly reduced by captopril, enalapril, SNAP, and 8‐pCPT‐cGMPs. The abilities of ACEIs and NO/PKG activation to inhibit AGE‐induced hypertrophic growth were verified by the observation that captopril, enalapril, SNAP, and 8‐pCPT‐cGMPs decreased protein levels of fibronectin, p21 Waf1/Cip1, and receptor for AGE. The results of the present study suggest that ACEIs significantly reduced AGE‐increased ERK/JNK/p38 MAPK activation and renal tubular hypertrophy partly through enhancement of the NO/PKG pathway. AGE‐induced ERK/JNK/p38 MAPK activation and attenuated nitric oxide signaling in human renal proximal tubular cells. ACEIs significantly inhibited hypertrophic growth and protein synthesis of receptor for AGE, fibronectin, and p21Waf1/Cip1.