Gα12 is required for renal cystogenesis induced by Pkd1 inactivation

Mutation of PKD1, encoding the protein polycystin-1 (PC1), is themain cause of autosomal dominant polycystic kidney disease (ADPKD). The signaling pathways downstream of PC1 in ADPKD are still not fully understood. Here, we provide genetic evidence for the necessity of G alpha 12 (encoded by Gna12, hereafter G alpha 12) for renal cystogenesis induced by Pkd1 knockout. There was no phenotype in mice with deletion of Ga12 (Ga12(-/-)). Polyinosine-polycytosine (pI: pC)-induced deletion of Pkd1 (Mx1Cre(+)Pkd1(f/f)G alpha 12(+/+)) in 1-week-old mice resulted in multiple kidney cysts by 9 weeks, but the mice with double knockout of Pkd1 and Ga12 (Mx1Cre(+)Pkd1(f/f)G alpha 12(-/-)) had no structural and functional abnormalities in the kidneys. These mice could survive more than one year without kidney abnormalities except multiple hepatic cysts in some mice, which indicates that the effect of G alpha 12 on cystogenesis is kidney specific. Furthermore, Pkd1 knockout promoted G alpha 12 activation, which subsequently decreased cell-matrix and cell-cell adhesion by affecting the function of focal adhesion and E-cadherin, respectively. Our results demonstrate that G alpha 12 is required for the development of kidney cysts induced by Pkd1 mutation in mouse ADPKD.