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

Qiyuan Zhuang,Fang Li,Jun Liu,Hongyu Wang,Yuchen Tian,Zhigang Zhang,Feng Wang,Zhonghua Zhao,Jianchun Chen,Huijuan Wu

doi:10.1038/s41374-020-00503-3

Abstract

AbstractFocal 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.An increase in podocyte apoptosis is positively correlated with the cytoplasmic distribution of YAP in focal segmental glomerulosclerosis (FSGS). YAP inhibition by verteporfin induces nuclear exclusion of YAP, thus increasing the podocyte apoptosis and accelerating disease progression. Therefore, this study suggests that YAP activation and nuclear distribution in podocytes is an endogenous anti-apoptotic mechanism during the progression of FSGS.

Highlights

The main manifestation of focal segmental glomerulosclerosis (FSGS) is nephrotic syndrome, a common chronic glomerular disease with poor clinical outcomes [1]
The results show that YAP is more evenly distributed in cytoplasm and nuclei of the cells around the glomeruli of normal renal tissue; in minimal change disease (MCD), YAP is mainly expressed in the nucleus of podocytes; while in FSGS, YAP is abundantly expressed and accumulated in the cytoplasm of podocytes (Fig. 1A; Supplementary Fig. 3A)
Since YAP is an anti-apoptotic protein that binds to the TEAD transcription factor to decrease cell death, we examined podocyte apoptosis in MCD and FSGS

Summary

Introduction

The main manifestation of focal segmental glomerulosclerosis (FSGS) is nephrotic syndrome, a common chronic glomerular disease with poor clinical outcomes [1]. Most of FSGS patients are cortisone-resistant, with a tendency to progress to end-stage renal disease [2]. Podocyte injury (including cytoskeleton impairment, hypertrophy and autophagy) and podocyte loss (including apoptosis and detachment), as well as exposure of glomeruli basement membrane, are critical mechanisms leading to the pathogenesis and progression of FSGS [3–5]. In diphtheria toxininduced mouse models, FSGS was observed histologically when the percentage of podocytes loss exceeded 20%. The degree of podocyte loss paralleled with the severity of proteinuria and the extent of renal function decline [6]. Since podocytes are highly differentiated and mature, preventing podocytes from injury and loss is of importance in order to slow or antagonize the progression of FSGS

Methods

Results

Conclusion