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Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis

Authors Wen S, Wang ZH, Zhang CX, Yang Y, Fan QL

Received 12 December 2019

Accepted for publication 16 January 2020

Published 10 February 2020 Volume 2020:13 Pages 313—323


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Konstantinos Tziomalos

Si Wen,1,* Zhao-Hua Wang,2,* Cong-Xiao Zhang,1 Ying Yang,1 Qiu-Ling Fan1

1Department of Nephrology, First Hospital of China Medical University, Shenyang, People’s Republic of China; 2Affiliated Dalian Friendship Hospital of Dalian Medical University, Dalian, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Qiu-Ling Fan
Department of Nephrology, First Hospital of China Medical University, No. 155 Nanjing Bei Street, Shenyang 110001, People’s Republic of China
Tel +86 13904012680

Background: Apoptosis has been repeatedly linked with diabetic kidney disease (DKD), which is a programmed cell death mediated by effector caspases-3, 6 and 7, targeting > 600 substrates. However, the pathophysiologic correlations of this process remain obscure. As a putative tumor suppressor, gasdermin E (GSDME) was recently reported to be cleaved by caspase-3 to produce a GSDME-N fragment which targets the plasma membrane to switch apoptosis to secondary necrosis. However, it remains elusive whether GSDME is involved in the regulation of DKD.
Methods: To evaluate the therapeutic potential of caspase-3 inhibition in DKD, we administered caspase-3 inhibitor Z-DEVD-FMK to STZ-induced diabetic mice for eight weeks. Albuminuria, renal function, pathological changes, and indicators of secondary necrosis and fibrosis were evaluated. In vitro, human tubule epithelial cells (HK-2 cells) were subjected to high-glucose treatment. Secondary necrosis was determined by LDH release, GSDME cleavage, and morphological feature under confocal microscopy. Z-DEVD-FMK and GSDME inhibition by shRNA were administered to suppress the cleavage and expression of GSDME. Flow cytometry, cytotoxicity assay and immunoblot were used to assess cell death and fibrogenesis.
Results: Caspase-3 inhibition by Z-DEVD-FMK ameliorated albuminuria, renal function, and tubulointerstitial fibrosis in diabetic mice. The nephroprotection mediated by Z-DEVD-FMK was potentially associated with inhibition of GSDME. In vitro, molecular and morphological features of secondary necrosis were observed in glucose-stressed HK-2 cells, evidenced by active GSDME cleavage, ballooning of the cell membrane, and release of cellular contents. Here we showed that caspase-3 inhibition prevented GSDME activation and cell death in glucose-treated tubular cells. Specifically, knocking down GSDME directly inhibited secondary necrosis and fibrogenesis.
Conclusion: These data suggest GSDME-dependent secondary necrosis plays a crucial role in renal injury, and provides a new insight into the pathogenesis of DKD and a promising target for its treatment.

Keywords: GSDME, DFNA5, secondary necrosis, diabetic kidney disease, Z-DEVD-FMK

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