Tubular Obstruction-Induced Polycystin Upregulation is Profibrotic and Induced a Severe Cystic Phenotype in Adult Mice with ADPKD
- Genetic Diseases: Cystic - Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
- Wu, Ming, Shuguang Hospital, Shanghai, China
Mutations in PKD1 or PKD2 gene cause ADPKD, however high levels of polycystins are detected in renal tissues of ADPKD patients. Animal studies showed that loss and gain of function of polycystins are both pathogenic and can induce cystic phenotype in the kidney, which are associated with enhanced renal fibrosis.
UUO or aristolochic acid I (AAI) induced mouse nepropathy was established for renal fibrosis study. Pkd1 or Pkd2 gene was inactivated in mice.
We demonstrated that polycystin-1 or polycystin-2 was highly expressed in fibrotic mouse kidneys and positively correlated with expression of collagen-I. Inhibition or deletion of polycystin-2 reduced the deposition of extracellular matrix proteins in fibrotic kidneys. Similarly, knockout of Pkd1 gene attenuated renal fibrosis in fibrotic mouse models. We further hypothesized that inhibition of polycystins delays cyst growth by mitigating renal fibrosis. Here, we showed that polycystin-1 or polycystin-2 was up-regulated in Pkd2 or Pkd1 mice respectively and tightly correlated with the growth of renal cysts and fibrosis development. Genetic deletion of both polycystin-1 and polycystin-2 retarded cyst growth in adult ADPKD mice. Finally, we inactivated Pkd1 gene in a fibrosis triggered adult ADPKD mouse model at different time point before or after the fibrotic injury. We showed that early and long-term inactivation of Pkd1 delayed fibrosis triggered renal cyst growth in adult Pkd1 mice as compared with mice with late and short-term inactivation of Pkd1 gene.
We conclude that tubular obstruction induced polycystin up-regulation is pro-fibrotic and accelerates cyst growth through enhancing renal interstitial fibrosis in ADPKD mice. Our study indicates that ADPKD is caused by the coexistence of loss and gain function of polycystins.