Abstract: TH-OR35
Ciliary ARL13B Is a Major Driver of Kidney Cystogenesis
Session Information
- Pediatric Nephrology: From Bench to Bedside
November 03, 2022 | Location: W307, Orange County Convention Center‚ West Building
Abstract Time: 05:33 PM - 05:42 PM
Category: Genetic Diseases of the Kidneys
- 1101 Genetic Diseases of the Kidneys: Cystic
Authors
- Van Sciver, Robert E., Emory University, Atlanta, Georgia, United States
- Gigante, Eduardo, Georgia Institute of Technology, Atlanta, Georgia, United States
- Caspary, Tamara, Emory University, Atlanta, Georgia, United States
Background
Polycystic kidney disease (PKD) is intricately linked to the primary cilium. PKD1 and PKD2 encode for polycystin proteins which localize to cilia, and mutations in these genes are causative for PKD. Mouse models predict the presence of a cilia-dependent cyst activating (CDCA) pathway that functions in cilia to drive cystogenesis. Despite the central importance of this organelle to renal cystic diseases, the ciliary driver(s) of cyst pathogenesis remain unknown. Mouse models have implicated that the ciliary GTPase ARL13B may be a major regulator of the CDCA pathway.
Methods
To directly test ARL13B’s role in the CDCA pathway, we engineered mice with an amino acid point mutation in ARL13B’s cilia-localization motif so the mice express cilia-excluded ARL13B from the endogenous locus. The resulting protein retains all known ARL13B biochemical functions, is stably expressed and is undetectable in cilia. Combining this mouse model with the kidney-specific loss Pkd1 allowed us to directly test ARL13B’s ciliary role in kidney cystogenesis.
Results
At 18-weeks, control kidneys had a kidney weight to body weight ratio (KW:BW) of 1.41±0.05. In adult induction mouse models, loss of ciliary ARL13B did not lead to cysts with a KW:BW of 1.40±0.03, while loss of Pkd1 led to severe cystic kidneys with KW:BW of 6.13±1.33. Loss of Pkd1 and ciliary exclusion of ARL13B suppressed the cystic phenotype caused by loss of Pkd1 alone with KW:BW of 2.13±0.16.
Conclusion
In adult induction models, loss of ciliary ARL13B suppresses the severe cystic kidney phenotype caused by loss of Pkd1 alone. These results directly implicate ciliary ARL13B as a major regulator of the CDCA pathway. Our findings indicate that ARL13B plays a critical role within the cilium in regulating kidney cystogenesis, with ciliary ARL13B activating a pro-cystogenic pathway.
Ciliary exclusion of ARL13B suppresses the severe cystic phenotype caused by loss of Pkd1.
Funding
- NIDDK Support