Gasdermin E Deletion Attenuates Ureteral Obstruction- and 5/6 Nephrectomy-Induced Renal Fibrosis and Kidney Dysfunction.

Mengying Wu,Yue Zhang,Songming Huang,Zhanjun Jia,Shuzhen Li,Qian Wang,Aihua Zhang,Qianqian Jin,Yuanyuan Li,Anning Zhou,Weiwei Xia

doi:10.3389/fcell.2021.754134

Abstract

Renal fibrosis contributes to kidney dysfunction in various chronic kidney diseases (CKDs). Renal fibrosis can be driven by renal tubular cell death and inflammation. Deletion of gasdermin E (GSDME), an executor of pyroptosis, has been reported to suppress renal tubular cell pyroptosis in several models of kidney injury. However, additional evidence confirming the role of GSDME in regulating renal fibrosis and kidney function in different CKDs is required. In our study, N-GSDME expression was significantly elevated in CKD models in vivo and in vitro. GSDME deletion alleviated renal fibrosis and inflammation in both unilateral ureteral ligation (UUO) and 5/6 nephrectomy (5/6Nx) models along with the attenuation of renal dysfunction. N-GSDME overexpression had a detrimental effect on fibrotic responses in UUO kidneys and TGF-β1-treated renal tubular epithelial cells. In addition, administration of caspase-3 inhibitor Z-DEVD-FMK, which inhibits caspase-3-mediated GSDME cleavage, protected against renal fibrosis both in vivo and in vitro. Collectively, these results provide evidence that the activation of GSDME is critical in regulating both renal fibrosis and kidney dysfunction possibly via promoting inflammatory responses in CKD. These findings may offer new insights into the identification of new therapeutic targets for protecting against CKDs.

Highlights

Chronic kidney disease (CKD) is a common chronic disease with a high prevalence and poor prognosis
To investigate whether gasdermin E (GSDME) is involved in the progression of CKD, we first determined the expression of full length GSDME (FL-GSDME) and its cleaved form, N-GSDME, in kidneys after unilateral ureteral ligation (UUO) for 7 days
Caspase-3, the enzyme that cleaves GSDME, was excessively activated (Figures 1E,F). These results suggest that GSDME cleaved by caspase-3 might be involved in the development of renal damage after UUO

Summary

Introduction

Chronic kidney disease (CKD) is a common chronic disease with a high prevalence and poor prognosis. CKD has become a global public health problem at present (Levey et al, 2007). Along with increased risk factors such as hypertension, obesity, and diabetes, the prevalence of CKD has increased recently and reached 13.4% worldwide. Tubule-interstitial fibrosis is widely accepted as the hallmark of CKD. The extent of this pathological process is closely related to the rate of functional decline, which determines the duration of end-stage renal disease (ESRD). Renal fibrosis is centrally implicated in CKD, and is characterized by atrophy of renal tubule epithelial cells and excessive production and accumulation

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Conclusion