Inhibition of transcriptional coactivator YAP Impairs the expression and function of transcription factor WT1 in diabetic podocyte injury

Kidney Int. 2024 Jun;105(6):1200-1211. doi: 10.1016/j.kint.2024.01.038. Epub 2024 Feb 27.

Abstract

Podocyte injury and loss are hallmarks of diabetic nephropathy (DN). However, the molecular mechanisms underlying these phenomena remain poorly understood. YAP (Yes-associated protein) is an important transcriptional coactivator that binds with various other transcription factors, including the TEAD family members (nuclear effectors of the Hippo pathway), that regulate cell proliferation, differentiation, and apoptosis. The present study found an increase in YAP phosphorylation at S127 of YAP and a reduction of nuclear YAP localization in podocytes of diabetic mouse and human kidneys, suggesting dysregulation of YAP may play a role in diabetic podocyte injury. Tamoxifen-inducible podocyte-specific Yap gene knockout mice (YappodKO) exhibited accelerated and worsened diabetic kidney injury. YAP inactivation decreased transcription factor WT1 expression with subsequent reduction of Tead1 and other well-known targets of WT1 in diabetic podocytes. Thus, our study not only sheds light on the pathophysiological roles of the Hippo pathway in diabetic podocyte injury but may also lead to the development of new therapeutic strategies to prevent and/or treat DN by targeting the Hippo signaling pathway.

Keywords: TEAD1; WT1; YAP; diabetic podocyte injury; podocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Diabetes Mellitus, Experimental* / complications
  • Diabetes Mellitus, Experimental* / metabolism
  • Diabetic Nephropathies* / etiology
  • Diabetic Nephropathies* / genetics
  • Diabetic Nephropathies* / metabolism
  • Diabetic Nephropathies* / pathology
  • Hippo Signaling Pathway
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins* / genetics
  • Phosphoproteins* / metabolism
  • Phosphorylation
  • Podocytes* / metabolism
  • Podocytes* / pathology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction*
  • TEA Domain Transcription Factors / metabolism
  • Tamoxifen / pharmacology
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • WT1 Proteins* / genetics
  • WT1 Proteins* / metabolism
  • YAP-Signaling Proteins* / metabolism

Substances

  • WT1 Proteins
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Adaptor Proteins, Signal Transducing
  • WT1 protein, mouse
  • Transcription Factors
  • Phosphoproteins
  • YAP1 protein, human
  • TEA Domain Transcription Factors
  • WT1 protein, human
  • Tead1 protein, mouse
  • Cell Cycle Proteins
  • TEAD1 protein, human
  • Tamoxifen
  • Protein Serine-Threonine Kinases
  • Nuclear Proteins