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Abstract: SA-PO412

Inhibition of YAP Impairs the Expression and Function of WT1 in Diabetic Podocytes

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Chen, Jianchun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Xiaoyong, Vanderbilt University Medical Center, 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

Podocyte injury and loss are hallmarks of diabetic nephropathy (DN). The molecular mechanisms underlying these phenomena are poorly understood. Yes-associated protein (YAP) is a transcriptional coactivator that regulates cell proliferation, differentiation, and apoptosis. Nuclear YAP in podocytes is crucial for differentiation, cell survival, and structural maintenance. However, the role of YAP in diabetic podocyte injury is unclear

Methods

Inducible podocyte-specific YAP deletion (YappodiKO) mice and wild-type(YappodWT) mice were generated by crossing podocin.iCreERT2(+) mice with Yap gene floxed mice. Unilateral nephrectomized (UNX) YappodiKO, YappodWT, FVB/NJ mice, and mice with an inactive allele of the Wt1 gene (Wt1CreERT2/+) were subjected to streptozotocin injections to induce type I diabetes. Proteinuria and diabetic podocyte injury were assessed. The expression of YAP, TAZ, WT1, TEAD1 and other podocyte-specific proteins in isolated glomeruli was analyzed by immunofluorescent staining or immunoblotting. The expression of these proteins was examined in primary cultured podocytes exposed to 25mM glucose with or without treatment of verteporfin, transfection of YAP siRNA or WT1 siRNA.

Results

In normal human and mouse kidneys, YAP was primarily localized in the nuclei of podocytes. However, diabetic podocytes exhibited increased phosphorylation and cytoplasmic retention of YAP. Diabetic UNX- YappodiKO and UNX- Wt1CreERT2/+ mice were more susceptible to diabetic podocyte injury, as evidenced by earlier proteinuria and severe glomerulosclerosis compared to diabetic UNX-wildtype control mice. In vivo and in vitro studies revealed that YAP is a crucial coactivator of TEAD for Wt1 gene transcription in podocytes, and TEAD1 is an unrecognized downstream target of WT1 in podocytes. In the presence of high glucose, inhibiting YAP in podocytes impaired WT1 expression, and subsequent inhibition of TEAD1 and other wt1 target gene expression may contribute to diabetic podocyte injury.

Conclusion

Constitutively active YAP in podocytes plays a vital role in regulating WT1 gene expression and controlling the transcriptional function of WT1. In diabetic podocytes, inhibition of active YAP impairs WT1 expression, and subsequent inhibition of TEAD1 expression may represent an unrecognized mechanism of diabetic podocyte injury.

Funding

  • NIDDK Support