Angiotensin II AT2 receptor regulates ureteric bud morphogenesis.
ANG II AT2 receptor (AT2R)-deficient mice exhibit abnormal ureteric bud (UB) budding, increased incidence of double ureters, and vesicoureteral reflux. However, the role of the AT2R during UB morphogenesis and the mechanisms by which aberrant AT2R signaling disrupts renal collecting system development have not been fully defined. In this study, we mapped the expression of the AT2R during mouse metanephric development, examined the impact of disrupted AT2R signaling on UB branching, cell proliferation, and survival, and investigated the cross talk of the AT2R with the glial-derived neurotrophic factor (GDNF)/c-Ret/Wnt11 signaling pathway. Embryonic mouse kidneys express AT2R in the branching UB and the mesenchyme. Treatment of embryonic day 12.5 (E12.5) metanephroi with the AT2R antagonist PD123319 or genetic inactivation of the AT2R 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 AT2R 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 AT2R stimulates apoptosis and inhibits proliferation of the UB cells in vivo. We conclude that AT2R performs essential functions during UB branching morphogenesis via control of the GDNF/c-Ret/Wnt11 signaling pathway, UB cell proliferation, and survival.
Song
Renfang
R
Section of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Spera
Melissa
M
Garrett
Colleen
C
El-Dahr
Samir S
SS
Yosypiv
Ihor V
IV
D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D009924:Organ Culture Techniques; D010750:Phosphoproteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014513:Ureter / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007093:Imidazoles; D008565:Membrane Proteins; D009842:Oligopeptides; D010750:Phosphoproteins; D011725:Pyridines; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; C425468:Spry1 protein, mouse; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse; D000804:Angiotensin II; C060894:CGP 42112A; C073402:PD 123319; D051096:Proto-Oncogene Proteins c-ret