Mutation of PKD1, encoding the protein polycystin-1 (PC1), is the main 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 Gα12 (encoded by Gna12, hereafter Gα12) for renal cystogenesis induced by Pkd1 knockout. There was no phenotype in mice with deletion of Gα12 (Gα12−/−). Polyinosine-polycytosine (pI:pC)-induced deletion of Pkd1 (Mx1Cre+Pkd1f/fGα12+/+) in 1-week-old mice resulted in multiple kidney cysts by 9 weeks, but the mice with double knockout of Pkd1 and Gα12 (Mx1Cre+Pkd1f/fGα12−/−) 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 Gα12 on cystogenesis is kidney specific. Furthermore, Pkd1 knockout promoted Gα12 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 Gα12 is required for the development of kidney cysts induced by Pkd1 mutation in mouse ADPKD.
The authors declare no competing or financial interests.
T.K. conceived and designed the study, and wrote the manuscript. W.Y and J.X.X. performed the majority of the experiments, analyzing data, preparing figures and editing of the manuscript. B.M.D, and J.Z. contributed to analyzing data and editing the manuscript. J.B. provided advice and assistance, and helped in critically reading and editing the manuscript. T.K managed the project, analyzed the data and carried out experiments. D.S. performed flow cytometry, immunostaining and took pictures for cell invasion and immunostaining. S.L., T.L., Q.W., M.T., W.Y., M.W. and I.E.B. aided in mouse genotyping, cell culture, PCR and western blotting, and assisted in animal dissections and husbandry. W.E.-J. collected human tissue and purified the cyst lining cells from ADPKD patients, and was responsible for editing and reviewing the manuscript and designing the statistics plan.
This work was supported by the National Institutes of Health [grant numbers K01 DK080179, 3K01DK080179 and DK096160 to T.K.; GM55223 to B.M.D.; R01DKD072381 and R37DK039773 to J.V.B.; DK51050 and DK099532 to J.Z.] and a grant from the Polycystic Kidney Center [P50 DK074030 to J.Z. and B.M.D.]. This project was also supported by the Baltimore Polycystic Kidney Disease Research and Clinical Core Center [grant number P30DK090868 to T.K.]. Deposited in PMC for release after 12 months.
- Received April 15, 2016.
- Accepted July 21, 2016.
- © 2016. Published by The Company of Biologists Ltd