Kidney Week

Abstract: FR-PO961

Deletion of Ift-A Gene, Thm1, Differentially Affects Cystic Kidney Disease in Pkd1 and Jck Mouse Models

Session Information

• PKD Cellular Pathogenesis, ARPKD, ADTKD, Ciliopathies
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Wang, Wei, University of Kansas Medical Center, Kansas City, Kansas, United States

Wei Wang,

• Silva, Luciane M., University of Kansas Medical Center, Kansas City, Kansas, United States

Luciane M. Silva,

• Allard, Bailey A., University of Kansas Medical Center, Kansas City, Kansas, United States

Bailey A. Allard,

• Maser, Robin L., University of Kansas Medical Center, Kansas City, Kansas, United States

Robin L. Maser,

• Tran, Pamela Vivian, University of Kansas Medical Center, Kansas City, Kansas, United States

Pamela Vivian Tran,

Background

Primary cilia are signaling organelles that are built and maintained by intraflagellar transport (IFT) complexes B and A. The role of primary cilia in renal cystic disease is poorly understood. Ciliary dysfunction causes renal cystic disease, yet ablation of cilia via Ift-B gene deletion and pharmacological shortening of cilia attenuated renal cystic disease in Pkd1 conditional knock-out (cko) and jck mutant mice, respectively. Such results suggest that cilia-mediated signaling within a renal cystic disease background may be pro-cystogenic. In contrast to deletion of an Ift-B gene, which often results in cilia loss, deletion of an Ift-A gene causes shortened cilia with protein accumulation in bulbous distal tips and can have opposing effects on signaling. Thus we examined the effect of Ift-A deficiency on a renal cystic disease background.

Methods

Using the ROSA-Cre^ERT recombinase, Thm1 was deleted together with Pkd1 in mice at 5 weeks of age, and in jck mutant mice at perinatal and postnatal (4 weeks) ages.

Results

Thm1 deletion attenuated Pkd1 cko renal cystic disease, decreasing BUN, cell proliferation, and P-STAT3 and P-ERK levels in Thm1;Pkd1 dko kidneys relative to Pkd1 cko kidneys. In contrast, Thm1 deletion caused a combinatorial effect in jck mice. While jck mice showed renal cysts of collecting duct and Loop of Henle tubular origins, perinatal deletion of Thm1 in jck mutants caused additional cysts of proximal tubular origin, and increased BUN. Deletion of Thm1 at 4 weeks of age in jck mutants did not affect proximal tubules, but did increase cell proliferation and BUN in Thm1; jck double mutant females. Renal P-STAT3 and P-ERK levels correlated with disease severity in all mutants. Additionally, primary cilia were elongated in jck mice, and Thm1 deletion in jck mice caused elongated cilia with IFT81 accumulation at the distal tips.

Conclusion

Attenuated renal cystic disease in Thm1;Pkd1 dko mice suggests that Pkd1 renal cystogenesis requires Ift-A, while the combinatorial effect in Thm1;jck double mutant kidneys suggests independent cyst-promoting roles for Thm1 and jck. The contrasting effects of Thm1 deletion in Pkd1 and jck mutants may reveal divergent mechanisms underlying Pkd1 and jck renal cystogenesis.

Funding

• NIDDK Support