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Kidney Week

Abstract: TH-OR106

Cystic Epithelial Cells Modify Their Microenvironment to Promote Fibrosis in Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Dwivedi, Nidhi, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Sinha, Sonali, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Calvet, James P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Rao, Reena, University of Kansas Medical Center, Kansas City, Kansas, United States
Background

Progressive tubulo-interstitial fibrosis accompanies cyst expansion in polycystic kidney disease (PKD) and is a major cause for loss of renal function and end stage renal disease. However, the mechanisms for development of renal fibrosis in PKD are currently unclear. A significant number of myofibroblasts, the primary producers of ECM, are often found in the pericystic areas in PKD kidneys. We tested the hypothesis that cystic epithelial cells can activate interstitial myofibroblasts and thus modify the cystic microenvironment to promote fibrosis.

Methods

Renal tubular epithelial-specific vasopressin type-2 receptors (V2R) were stimulated or inhibited in pre-weaning and adult inducible conditional Pkd1 gene knockout mice with cystic kidneys. Wild type and PKD mice were treated with the V2R agonist dDAVP, or the antagonist OPC31260 by daily intraperitoneal injections for 3 days.

Results

Treatment with dDAVP increased myofibroblast numbers and ECM deposition in PKD mouse kidneys, while OPC31260 had the opposite effect. Expression of connective tissue growth factor (CTGF), a matricellular protein, and its transcriptional regulator YAP were increased in the dDAVP treated PKD mouse kidneys. CTGF and YAP were expressed in mouse and human ADPKD renal cystic epithelium, and CTGF secreted by cultured human ADPKD epithelial cells induced myofibroblast activation and migration in vitro. In contrast, YAP inactivation by pharmacological inhibition or renal tubule specific gene deletion suppressed CTGF production and cyst expansion in vitro, and the development of fibrosis in Pkd1 knock out mice.

Conclusion

These results suggest that epithelial specific V2R stimulation can induce YAP dependent CTGF production to activate interstitial myofibroblasts and renal fibrosis in PKD.

Funding

  • NIDDK Support