Nuclear exclusion of YAP exacerbates podocyte apoptosis and disease progression in Adriamycin-induced focal segmental glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is a chronic glomerular disease with poor clinical outcomes. Podocyte loss via apoptosis is one important mechanism underlying the pathogenesis of FSGS. Recently, Yes-associated-protein (YAP), a key downstream protein in the Hippo pathway, was identified as an activator for multiple gene transcriptional factors in the nucleus to control cell proliferation and apoptosis. To investigate the potential role of YAP in the progression of FSGS, we examined kidney samples from patients with minimal change disease or FSGS and found that increases in podocyte apoptosis is positively correlated with the cytoplasmic distribution of YAP in human FSGS. Utilizing an established mT/mG transgenic mouse model and primary cultured podocytes, we found that YAP was distributed uniformly in nucleus and cytoplasm in the podocytes of control animals. Adriamycin treatment induced gradual nuclear exclusion of YAP with enhanced phospho-YAP/YAP ratio, accompanied by the induction of podocyte apoptosis both in vivo and in vitro. Moreover, we used verteporfin to treat an Adriamycin-induced FSGS mouse model, and found YAP inhibition by verteporfin induced nuclear exclusion of YAP, thus increasing podocyte apoptosis and accelerating disease progression. Therefore, our findings suggest that YAP nuclear distribution and activation in podocytes is an important endogenous anti-apoptotic mechanism during the progression of FSGS.

Adriamycin-Induced Podocyte Injury Disrupts the YAP-TEAD1 Axis and Downregulates Cyr61 and CTGF Expression

“…Although we did not observe differences in the subcellular localization of YAP before and after ADR treatment, the strong nuclear localization of YAP we observed in the hiPSC-podocytes led us to investigate the expression of YAP’s nuclear cofactors, the TEAD family transcription factors. While others have reported that nuclear YAP is indispensable for human podocyte survival, , it remains unclear which genetic programs YAP is directing in these cells. Thus, we reasoned that studying the YAP-TEAD axis may yield additional insight into the tissue-specific activities of YAP in both injured and healthy podocytes.…”

“…This nuclear translocation appeared to induce podocyte cell-cycle re-entry and dedifferentiation, an effect we did not observe in this study. It should be noted that in vivo , YAP localization is primarily cytoplasmic in healthy murine podocytes , but nuclear in human podocytes. , In addition to species-specific differences in YAP regulation, matrix stiffness can also govern YAP localization, and thus the activity of downstream YAP targets. In 2018, Bonse and colleagues demonstrated that nuclear YAP is a key regulator of human podocyte survivalwhen the authors plated podocytes on soft matrices (<12 kPa), YAP localized to the cytoplasm, leading to cell detachment and death .…”

“…To overcome some of these limitations, we used our previously established model of mature hiPSC-podocytes to study the expression of signaling factors thought to influence human podocyte biology and injury response. Specifically, we examine the expression of YAP and its downstream effectors due to mounting evidence that nuclear-localization of YAP is necessary for podocyte survival. − , However, it remains unclear which genetic programs YAP is regulating to confer these pro-survival effects. To the best of our knowledge, this study is the first to examine the downstream effectors of the YAP signaling axis using mature, human stem cell-derived podocytes.…”

The FSGS disease gene product and nuclear pore protein NUP205 regulates nuclear localization and activity of the transcriptional regulators YAP and TAZ in podocytes

“…20,21 Therefore, podocyte homeostasis relies on a well-balanced nuclear shuttling and activity of YAP and TAZ, a process whose regulation is so far not well understood. 19,[22][23][24][25][26][27] Here, we explore the interactome of YAP and TAZ in an in vitro mouse podocyte model. We identify several nuclear transport components that associate in protein complexes with both YAP and TAZ.…”

hucMSC-sEVs-Derived 14-3-3ζ Serves as a Bridge between YAP and Autophagy in Diabetic Kidney Disease

“…Phosphorylation of a key serine (Ser 127) of YAP in mammals confines the protein to the cytoplasm and no longer takes effects in target gene expression, which is regulated by 14-3-3 ζ protein [ 26 ]. YAP has been confirmed to be closely related to renal fibrosis [ 22 , 27 ], cell apoptosis [ 28 ], and epithelial-mesenchymal transition [ 29 ]. Previous study by our team has confirmed that the hucMSC-sEVs-derived 14-3-3 ζ coordinated the Wnt signaling pathway by regulating YAP during skin regeneration [ 30 ].…”