Kidney Week

Abstract: FR-OR102

Conditional Knockout of YAP Decreases Podocyte Adhesion and Exacerbates FSGS Progression Through α3β1 Integrin

Session Information

• Podocytopathy: Novel Insights and Emerging Therapeutic Targets
  November 03, 2023 | Location: Room 108, Pennsylvania Convention Center
  Abstract Time: 05:06 PM - 05:15 PM

Category: Glomerular Diseases

• 1403 Podocyte Biology

Authors

• Shao, Guangze, Fudan University School of Basic Medical Sciences, Shanghai, China

Guangze Shao, PhD

• Xu, Jitu, Fudan University School of Basic Medical Sciences, Shanghai, China

Jitu Xu,

• Xu, Yanyong, Fudan University School of Basic Medical Sciences, Shanghai, China

Yanyong Xu,

• Wu, Huijuan, Fudan University School of Basic Medical Sciences, Shanghai, China

Huijuan Wu,

Background

The occurrence of proteinuria in FSGS patients is closely related to the decreased adhesion and further loss of podocytes. Previous studies showed YAP nuclear exclusion contributes to podocyte apoptosis and FSGS progression, but its role in the podocyte adhesion remains unclear.

Methods

We generated podocyte-specific Yap gene knockout mice (Yap^podoKO) by crossing Yap^flox/flox mice with NPHS2-Cre mice. We then constructed Adriamycin induced FSGS model by using Yap^podoKO mice and control mice. Furthermore, we treated the above mice with pyrintegrin, an agonist of α3β1 integrin.

Results

By 16 weeks of age, compared to Yap^flox/flox mice, Yap^podoKO mice developed decreased podocyte adhesion including reduced α3β1 integrin and focal adhesion (examined by double immunofluorescence staining of vinculin and F-actin), with effacement of a few of foot process under the electron microscopy, although showed no significant difference in morphology by light microscopy, proteinuria, serum creatinine and BUN. Compared to Adriamycin treated Yap^flox/flox mice, Yap^podoKO mice aberrantly aggravated decrease in α3β1 integrin, focal adhesion and podocyte number induced by Adriamycin, with markedly increased segmental or global glomerulosclerosis, foot process effacement and proteinuria. Of note, pyrintegrin treatment largely improved the podocyte adhesion and ameliorated the disease progression of FSGS caused by Adriamycin treatment with or without podocyte-specific Yap knockout.

Conclusion

This study, for the first time, demonstrated that podocyte-specific Yap gene knockout can reduce podocyte adhesion thus aggravating the process of FSGS via α3β1 integrin. This is important to report because, so far, there is no clinical strategy to treat FSGS by targeting α3β1 integrin and its regulatory factors.