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Abstract: FR-OR004

Deletion of Ift-A Gene, Thm1, in a Pkd2 Early-Onset ADPKD Mouse Model Has Renal Tubular-Specific Attenuating and Synergistic Effects

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

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

Primary cilia are signaling organelles that have emerged as powerful modifiers of ADPKD. Primary cilia are synthesized by intraflagellar transport (IFT) complexes B and A. Ift-B gene deletion in renal tubules in Pkd1 or Pkd2 conditional knock-out (cko) mice ablated primary cilia and attenuated renal cystic disease, suggesting that cilia-mediated signaling within an ADPKD background may be pro-cystogenic. In contrast to Ift-B gene deletion, which often results in cilia loss, Ift-A gene deletion 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 Pkd2 mutant background.

Methods

Using the ROSA-CreERT recombinase, Pkd2 and Thm1 were globally deleted alone or together in mice at postnatal day (P) 0 generating early-onset disease models, which were analyzed at P21.

Results

At P21, Thm1 cko kidneys were similar to those of control littermates. Pkd2;Thm1 double knock-out (dko) mice had reduced KW/BW ratios and smaller collecting duct-derived cysts than Pkd2 cko mice. Yet BUN levels were similar between Pkd2;Thm1 dko and Pkd2 cko mice. Unlike Pkd2 and Thm1 single mutants, Pkd2;Thm1 dko mice developed proximal tubular-derived cysts. Additionally, Pkd2;Thm1 dko kidneys showed enhanced fibrosis and STAT3 activation relative to Pkd2 cko kidneys. In Pkd2;Thm1 dko collecting ducts, many primary cilia were shortened with accumulation of IFT81 protein at the distal tip, characteristic of an IFT-A cilia mutant phenotype and in contrast to Pkd2 cko collecting duct primary cilia, which were lengthened.

Conclusion

In Pkd2;Thm1 dko mice, reduced KW/BW ratios and collecting duct-derived cysts indicate that IFT-A is required for a component of Pkd2 renal cystogenesis. Yet the presence of proximal tubular-derived cysts reveals there is also synergy between Pkd2 and Thm1 deletion. Further, enhanced renal fibrosis and STAT3 activation indicate that Thm1 deletion exacerbates Pkd2-mutant renal disease. Thus the role of Thm1 or IFT-A deficiency on an ADPKD background may be renal tubular/cell-specific.