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Abstract: FR-PO386

The Hippo Pathway in the Regulation of the Epithelial-to-Mesenchymal Transition of Renal Proximal Tubular Epithelial Cell in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Qi, Chenyang, School of Basic Medical Sciences, Fudan University, Shanghai, China
  • Zhang, Zhigang, School of Basic Medical Sciences, Fudan University, Shanghai, China
  • Wu, Huijuan, School of Basic Medical Sciences, Fudan University, Shanghai, China
Background

Diabetic nephropathy (DN) is a major cause of end-stage renal disease in the world. Epithelial-to-mesenchymal transition (EMT) of renal proximal tubular epithelial cells (PTECs) is an important mechanism in the progression of interstitial fibrosis in DN. Recently, Hippo pathway was recognized as a regulator of cell proliferation, differentiation and apoptosis and may be potential therapeutic targets in many kidney diseases.

Methods

In order to study whether the Hippo pathway regulate EMT of PTECs in DN, we cultivated the db/db type 2 diabetic model mice and normal or high glucose stimulated HK-2 cells (human PTECs). We detected the levels of Hippo pathway and EMT of HK-2 cells and PTECs in db/db mice. We administrated verteporfin, a YAP inhibitor, and detected the change of EMT.

Results

Compared with the littermates, db/db mice developed microalbuminuria at the age of 20 weeks and showed obvious kidney hypertrophy from the 4th week. Then, we found that the expression of phosphorylated YAP at serine 127 (p-YAP-S127) in PTECs was obviously increased. While, the total YAP level did not change significantly. We also found that the protein levels of epithelial markers (Ecadherin, ZO-1, and CK-18) were significantly decreased in db/db mice, while the mesenchymal markers (Vimentin, α-SMA) was elevated and these changes were consistent with EMT. Similar changes have been found in HK-2 cells. In high glucose stimulated HK-2 cells, p-YAP-S127/total YAP ratio was increased, epithelial markers were decreased and the mesenchymal markers was elevated (i.e., the onset of EMT). At the same time, we extracted the nuclear and cytoplasmic fraction in normal or high glucose stimulated HK-2 cells. The total YAP level in the cytoplasm was increased, while that in the nucleus was decreased. In addition, administration of verteporfin, which could reduce the level of p-YAP, elevated the epithelial markers and decreased mesenchymal markers (i.e., reversed the EMT) in high glucose stimulated HK-2 cells.

Conclusion

In conclusion, high glucose reduced the YAP nuclear translocation, thus more p-YAP was anchored in the cytoplasm and induced EMT of PTECs. Verteporfin could reverse the EMT, which suggested that Hippo pathway can regulate the EMT in PTECs. This study would provide a new potential therapeutic target for DN.

Funding

  • Government Support - Non-U.S.