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

Jianchun Chen; Xiaoyong Wang; Qian He; Hai-Chun Yang; Agnes B Fogo; Raymond C Harris

doi:10.1016/j.kint.2024.01.038

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

Kidney Int. 2024 Feb 27:S0085-2538(24)00160-1. doi: 10.1016/j.kint.2024.01.038. Online ahead of print.

Authors

Jianchun Chen¹, Xiaoyong Wang², Qian He², Hai-Chun Yang³, Agnes B Fogo³, Raymond C Harris⁴

Affiliations

¹ Department of Veterans Affairs, Nashville, Tennessee, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Vanderbilt Center for Kidney Disease, Nashville, Tennessee, USA. Electronic address: Jian-chun.chen@vumc.org.
² Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴ Department of Veterans Affairs, Nashville, Tennessee, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Vanderbilt Center for Kidney Disease, Nashville, Tennessee, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

PMID: 38423183
DOI: 10.1016/j.kint.2024.01.038

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 (Yap^podKO) 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.