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Abstract: FR-PO220

YAP Activation in Renal Proximal Tubule Epithelial Cells Contributes to Development of Tubulointerstitial Fibrosis in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Chen, Jianchun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Zhang, Ming-Zhi, Vanderbilt University Medical School, Nashville, Tennessee, United States
  • Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Excessive production of CTGF in kidney has been implicated in the development and progression of DN. YAP (Yes-associated protein) is a transcription factor activator for multiple critical transcription factors. The goal of these studies is to determine the potential role and underlying mechanisms of YAP activation in renal proximal tubule epithelial cells (RPTC) during DN development and progression.

Methods

YAP activation in RPTC was evaluated in deidentified diabetic patient and control kidneys, type I and II diabetic mouse kidneys and cultured human renal proximal tubule epithelial cells (hRPTC). Unilateral nephrectomized (UNX) inducible RPTC specific YAP deletion (YapptiKO) and wild type (YapptWT) mice, FVB/NJ or eNOS-/- mice were subjected to streptozotocin injections to induce type I diabetes. The diabetic mice were treated with or without verteporfin (a YAP-TEAD association inhibitor), Y-27632 (a Rho association Kinase (ROCK) inhibitor). Mouse urinary albumin excretion and tubulointerstital fibrosis were evaluated. Expressions of YAP, CTGF and profibrotic or fibrotic proteins in RPTC were analyzed. hRPTC was exposed to 25mM glucose treated with or without verteporfin or Y-27632, or YAP, RhoA GTPase siRNA followed by analysis of YAP activation.

Results

YAP expression and nuclear translocation were upregulated in the RPTC of kidneys from diabetic patients and type I and type II diabetic mice, or in the hRPTC exposed to culture medium containing 25mM of glucose. RPTC specific YAP deletion, or treatment of the diabetic eNOS-/- or FVB/NJ mice with verteporfin or Y-27632 inhibited CTGF and α-SMA expression in diabetic renal cortical tissues and attenuated tubulointerstitial collagen I deposition. Proteinuria was ameliorated in verteporfin or Y-27632 treated mice but not in YapptiKO mice. Y-27632 treatment also decreased YAP activation in diabetic RPTC. In hRPTC, inhibition of YAP activation blocked CTGF and inhibition of RhoA GTPase attenuated YAP and CTGF expression in response to high glucose.

Conclusion

RhoA GTPase-dependent YAP activation and subsequent increases in CTGF and ECM production mediated myofibroblast transition may be potential underlying mechanisms for diabetic tubulointerstitial fibrosis and targeting YAP activation may serve as a therapeutic intervention in diabetic nephropathy.

Funding

  • NIDDK Support