Angiotensin II AT(2) receptor regulates ureteric bud morphogenesis

作者：Song Renfang; Spera Melissa; Garrett Colleen; El Dahr Samir S; Yosypiv Ihor V^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2010, 298(3): F807-F817.

DOI：10.1152/ajprenal.00147.2009

• angiotensin
• GDNF
• c-Ret

Song R, Spera M, Garrett C, El-Dahr SS, Yosypiv IV. Angio-tensin II AT(2) receptor regulates ureteric bud morphogenesis. Am J Physiol Renal Physiol 298: F807-F817, 2010. First published December 23, 2009; doi:10.1152/ajprenal.00147.2009.-ANG II AT(2) receptor (AT(2)R)-deficient mice exhibit abnormal ureteric bud (UB) budding, increased incidence of double ureters, and vesicoureteral reflux. However, the role of the AT(2)R during UB morphogenesis and the mechanisms by which aberrant AT(2)R signaling disrupts renal collecting system development have not been fully defined. In this study, we mapped the expression of the AT(2)R during mouse metanephric development, examined the impact of disrupted AT(2)R signaling on UB branching, cell proliferation, and survival, and investigated the cross talk of the AT(2)R with the glial-derived neurotrophic factor (GDNF)/c-Ret/Wnt11 signaling pathway. Embryonic mouse kidneys express AT(2)R in the branching UB and the mesenchyme. Treatment of embryonic day 12.5 (E12.5) metanephroi with the AT(2)R antagonist PD123319 or genetic inactivation of the AT(2)R in mice inhibits UB branching, decreasing the number of UB tips compared with control (34 +/- 1.0 vs. 43 +/- 0.6, P < 0.01; 36 +/- 1.8 vs. 48 +/- 1.3, P < 0.01, respectively). In contrast, treatment of metanephroi with the AT(2)R agonist CGP42112 increases the number of UB tips compared with control (48 +/- 1.8 vs. 39 +/- 12.3, P < 0.05). Using real-time quantitative RT-PCR and whole mount in situ hybridization, we demonstrate that PD123319 downregulates the expression of GDNF, c-Ret, Wnt11, and Spry1 mRNA levels in E12.5 metanephroi grown ex vivo. AT(2)R blockade or genetic inactivation of AT(2)R stimulates apoptosis and inhibits proliferation of the UB cells in vivo. We conclude that AT(2)R performs essential functions during UB branching morphogenesis via control of the GDNF/c-Ret/Wnt11 signaling pathway, UB cell proliferation, and survival.

• 出版日期2010-3