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Kidney Week

Abstract: PO1552

Low-Dose Repeated Cisplatin-Induced Renal Injury Promotes Cyst Formation in Both Cilia Mutant and PC2 Mutant Mouse Models

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Li, Zhang, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Haycraft, Courtney J., The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Aloria, E.j., The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Yoder, Bradley K., The University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Multiple renal cystic diseases, including PKD, are caused by dysfunction of the primary cilium on the tubule epithelium. Links between cilia dysfunction, cyst formation, and renal injuries have been reported. In animal models, injury (e.g. ischemia reperfusion) exacerbated the rate of cyst formation.
Cisplatin is an antitumor drug used widely in treatment of varieties of malignancies that also has severe nephrotoxicity side effects. Here we evaluate whether a second form of renal injury induced by a low dose of Cisplatin also leads to mal-repair of the kidney and to increased cyst formation in mouse models with cilia function perturbation.

Methods

To test the effects of cisplatin-induced renal injury on cyst formation, we utilized a low-dose repeated cisplatin protocol (5.0mg/kg BW; IP once a week for 4 weeks) on adult-induced conditional Ift88 and PC2 mutant mice. We preformed IF staining for the injury marker kim1 and flow cytometry analysis of immune cells from WT and cilia dysfunctional kidneys 3 days after 2° cisplatin treatment to evaluate renal injury. Cyst index were analyzed at 5 weeks in PC2 mutant and at 9 weeks in Ift88 mutant after the final dose.

Results

Low-dose repeated cisplatin treatment resulted in increased kim1 expression, mainly in the cortex, compared to vehicle treatment group in both Ift88 mutant and PC2 mutant mice compared to control. Analysis of flow cytometry data showed that there was minimal immune cell accumulation, including macrophages, NK, B or T cells, at 3 days after 2° cisplatin injection, similar to that in controls. Additional time points are currently being evaluated.
While we did not observe major changes in immune cell response at the earlier time point prior to cyst formation, in both PC2 and Ift88 mutants there was a marked increase in cyst severity, accompanied with massive immune cell accumulation compared to vehicle treated mutants at 5 and 9 weeks after the final cisplatin injection, respectively.

Conclusion

These data indicate cilia function is important in regulating repair processes following injury, defects in which contribute to more aggressive rates of cystogenesis. Additionally, it suggests multiple forms of injury induce cyst formation and that the cisplatin protocol could be used as an alternative approach to IRI to accelerate cyst formation in PKD animal models.

Funding

  • NIDDK Support