ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO478

Suppression of the Hippo Pathway in Tubular Cells Leads to Renal Fibrosis in Mice

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Xu, Chunhua, The Chinese University of Hong Kong, Hong Kong, China
  • Wang, Yang, The Chinese University of Hong Kong, Hong Kong, China
  • Wang, Li, The Chinese University of Hong Kong, Hong Kong, China
  • Mak, King lun kingston, Guangzhou Regenerative Medicine and Health-Guangdong Laboratory, Guangzhou, China
  • Huang, Yu, The Chinese University of Hong Kong, Hong Kong, China
  • Xia, Yin, The Chinese University of Hong Kong, Hong Kong, China
Background

The Hippo pathway controls organ size and tumorigenesis. The core components of the Hippo pathway consist of Mammalian Ste20-like kinases 1/2 (MST1/2) and their scaffold protein SAV1, large tumor suppressor 1/2 (LATS1/2) and their scaffold proteins MOB1A/1B, and two downstream effectors YAP/TAZ. Several components of the Hippo pathway, including SAV1, LATS1/2, and YAP/TAZ, have been found to be critically involved in embryonic kidney development or kidney disease. However, the role of MST1 and MST2 in kidney remains unknown.

Methods

We generated tubular cell specific Mst1/Mst2 double knockout mice by intercrossing floxed Mst1/Mst2 mice with Ksp-Cre transgenic mice. The Hippo pathway is restrained in renal tubular epithelium in Mst1/Mst2 mutant mice.

Results

We showed for the first time that MST1 and MST2 were highly expressed in all nephron segments and collecting ducts in mouse kidneys. Deletion of Mst1/Mst2 (Mst1f/f;Mst2f/f;Ksp-Cre) in mouse renal tubular epithelium resulted in increased kidney sizes starting from 4 weeks of age, coupled with increased YAP activity and cell proliferation in renal tubules. The Mst1/Mst2 mutant mice developed chronic kidney disease as indicated by progressive increases in tubular damage, inflammation, fibrosis and functional impairment. Deletion of Yap prevented kidney overgrowth and tubular damage in Mst1/Mst2 mutant mice and rescued the expression of many inflammatory factors measured at 4 weeks of age. More importantly, ablation of Yap prevented fibrosis development in Mst1/Mst2 mutant mice at 8 weeks of age.

Conclusion

We found that suppression of the Hippo pathway in renal tubular epithelium results in renal fibrosis via activation of YAP.

Funding

  • Government Support - Non-U.S.