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

Abstract 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 H 2 O 2 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 H 2 O 2 and EGF. The effect of leptin was also prevented by the inhibitor of Src tyrosine kinase, PP2. Leptin and H 2 O 2 increased Src phosphorylation at Tyr 418 . We conclude that leptin-induced stimulation of renal Na + , K + -ATPase involves H 2 O 2 generation, Src kinase, transactivation of the EGF receptor, and stimulation of ERK.