H2O2 and Src-dependent transactivation of the EGF receptor mediates the stimulatory effect of leptin on renal ERK and Na+, K+-ATPase

We examined the mechanism through which leptin increases Na+, K+-ATPase activity in the rat kidney. Leptin was infused under anaesthesia into the abdominal aorta proximally to the renal arteries and then Na+, K+-ATPase activity was measured in the renal cortex and medulla. Leptin (1 μg/kg min) increased Na+, K+-ATPase activity after 3 h of infusion, which was accompanied by the increase in urinary H2O2 excretion and phosphorylation level of extracellular signal regulated kinase (ERK). The effect of leptin on ERK and Na+, K+-ATPase was abolished by catalase, specific inhibitors of epidermal growth factor (EGF) receptor, AG1478 and PD158780, as well as by ERK inhibitor, PD98059, and was mimicked by both exogenous H2O2 and EGF. The effect of leptin was also prevented by the inhibitor of Src tyrosine kinase, PP2. Leptin and H2O2 increased Src phosphorylation at Tyr418. We conclude that leptin-induced stimulation of renal Na+, K+-ATPase involves H2O2 generation, Src kinase, transactivation of the EGF receptor, and stimulation of ERK.