Mutations of the renin-angiotensin system (RAS) genes are associated with congenital abnormalities of the kidney and urinary tract. We have shown that angiotensin (Ang) II stimulates ureteric bud (UB) branching in vitro. The present study tested the hypothesis that Ang II stimulates the GDNF/c-Ret/Wnt11 pathway. E12.5 mice metanephroi were grown for 24 hours in the presence or absence of Ang II or AT1R receptor antagonist candesartan and subjected to whole-mount ISH. c-Ret, a receptor tyrosine kinase for GDNF, and its downstream target Wnt11 were induced by Ang II in the UB tip cells. GDNF, a Wnt11-regulated gene expressed in the mesenchyme, was also upregulated by Ang II. In contrast, Ang II treatment downregulated Spry1, an endogenous inhibitor of Ret tyrosine kinase activity, in an AT1R-dependent manner. Quantitative RT-PCR analysis confirmed that Ang II decreases Spry1 mRNA levels in cultured UB cells. In vivo BrdU incorporation indicated that exogenous Ang II preferentially stimulates UB tip cell proliferation, while AT1R blockade increases TUNEL-positive apoptotic cells. These findings suggest a model in which AT1R-mediated inhibition of Spry1 gene expression releases c-Ret tyrosine kinase activity leading to upregulation of c-Ret and its downstream target gene, Wnt11. Enhanced Wnt11 expression induces GDNF in the adjacent mesenchyme. This causes focal bursts of UB tip cell proliferation, a decrease in UB tip cell apoptosis and branching.