Deficiency of intrarenal angiotensin II type 2 receptor impairs paired homeo box-2 and N-myc expression during nephrogenesis.
We previously demonstrated that angiotensin II (Ang II) stimulates paired homeo box-2 (Pax-2) via the Ang II type 2 receptor (AT(2)R). The Pax-2 gene and N-myc play pivotal roles in renal morphogenesis via their effects on cell proliferation and differentiation in embryonic mesenchymal cells and embryonic mouse kidneys. Since AT(2)R knock-out (KO) mice have a phenotype that is similar to that of humans with congenital renal and urinary tract anomalies (CAKUT) and develop hypertension in adulthood, these mice and wild-type controls were used for this study. Embryonic kidneys isolated from E12 to term gestation were cultured in Dulbecco's modified Eagle's medium (DMEM) with or without Ang II (10(-6) M) for 24 h ex vivo. Renal morphogenesis was histologically assessed. Mean glomerular tuft volume was determined by the method of Weibel and Gomez with the aid of image analysis software. Pax-2 and N-myc gene expression were determined by immunostaining as well as by Western blotting and real-time-quantitative polymerase chain reaction (RT-qPCR). Glomerular size was significantly smaller, and Pax-2 and N-myc expression down-regulated, in kidneys of AT(2)R KO mice compared with those of wild-type mice. In ex vivo studies, Ang II stimulated Pax-2 and N-myc mRNA expression in embryonic kidneys of wild-type mice, but this stimulatory effect was absent in embryonic kidneys of AT(2)R KO mice. Taken together, these data indicate that intrarenal AT(2)R plays an important role in nephrogenesis. Deficiency of AT(2)R may impair both Pax-2 and N-myc expression, eventually resulting in glomerular hyperfiltration that may, ultimately, lead to later development of hypertension.
Chen
Yun-Wen
YW
Research Centre, Centre hospitalier de l'Université de Montréal -Hôtel-Dieu, Pavillon Masson, Montreal, Quebec, H2W 1T7, Canada.
Tran
Stella
S
Chenier
Isabelle
I
Chan
John S D
JS
Ingelfinger
Julie R
JR
Inagami
Tadashi
T
Zhang
Shao-Ling
SL
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D016259:Genes, myc; D007668:Kidney / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D051762:PAX2 Transcription Factor / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000502:physiology*
D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II