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Kidney Week

Abstract: TH-PO894

Inhibition of Yap/Taz Ameliorates Renal Fibrosis in Type 2 Diabetic Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wang, Yu, The Chinese University of Hong Kong, Hong Kong, China
  • Wang, Li, The Chinese University of Hong Kong, Hong Kong, China
  • Shang, Wenbin, The Chinese University of Hong Kong, Hong Kong, China
  • Xu, Chunhua, The Chinese University of Hong Kong, Hong Kong, China
  • Xia, Yin, The Chinese University of Hong Kong, Hong Kong, China
  • Huang, Yu, The Chinese University of Hong Kong, Hong Kong, China
Background

Yap/Taz are central mediators of the Hippo pathway, which have been found to be involved in the pathogenesis of chronic kidney disease including diabetic nephropathy. The expression of Yap increases in both the kidney of diabetic mice and the renal proximal tubule epithelial cells in response to high glucose. However, the underlying mechanism of Yap/Taz in renal fibrosis remains largely unknown.

Methods

The HK2 cell line (human proximal renal tubular epithelial cells) were challenged by advanced glycation end-products (AGEs) for 48 hours. Cells were harvested for RT-PCR.
Diabetic mice (db/db) and their control counterparts (db/+) were gavaged with atorvastatin (10 mg/kg/day for 2 months). Urine was collected by metabolic cages. At sacrifice, kidneys were harvested for Periodic Acid-Schiff staining, Masson's trichrome staining, and immunostaining. Expression of target proteins and genes were analyzed by Western blot and RT-PCR.

Results

In the present study, we found that the elevated expression of Yap/Taz target genes (CTGF and CYR61), COL1A1 and FN in HK2 cells after exposure to AGEs for 48 hours. Besides, the expression of Yap increased in the kidney of db/db mice. By contrast, oral treatment of db/db mice with atorvastatin (10 mg/kg/daily), a lipid-lowering drug with newly identified YAP inhibitory property, ameliorated albuminuria, glomerular hypertrophy, and renal fibrosis in diabetes. Atorvastatin suppressed the activity of YAP and TAZ as well as the expression of collagen 1, fibronectin, α-SMA and vimentin in the kidney of db/db mice.

Conclusion

In summary, atorvastatin is effective in ameliorating renal fibrosis probably in part through suppressing the activity of Yap in type 2 diabetic mice.

Funding

  • Government Support - Non-U.S.