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

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...

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Autores principales:	Wen S, Wang ZH, Zhang CX, Yang Y, Fan QL
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	gsdme dfna5 secondary necrosis diabetic kidney disease z-devd-fmk Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/8a2c8d8cdce442048352e44a66b7765e
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spelling	oai:doaj.org-article:8a2c8d8cdce442048352e44a66b7765e2021-12-02T06:22:00ZCaspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis1178-7007https://doaj.org/article/8a2c8d8cdce442048352e44a66b7765e2020-02-01T00:00:00Zhttps://www.dovepress.com/caspase-3-promotes-diabetic-kidney-disease-through-gasdermin-e-mediate-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Si 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 workCorrespondence: Qiu-Ling FanDepartment of Nephrology, First Hospital of China Medical University, No. 155 Nanjing Bei Street, Shenyang 110001, People’s Republic of ChinaTel +86 13904012680Email cmufql@163.comBackground: 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-FMKWen SWang ZHZhang CXYang YFan QLDove Medical Pressarticlegsdmedfna5secondary necrosisdiabetic kidney diseasez-devd-fmkSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 13, Pp 313-323 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	gsdme dfna5 secondary necrosis diabetic kidney disease z-devd-fmk Specialties of internal medicine RC581-951
spellingShingle	gsdme dfna5 secondary necrosis diabetic kidney disease z-devd-fmk Specialties of internal medicine RC581-951 Wen S Wang ZH Zhang CX Yang Y Fan QL Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis
description	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 workCorrespondence: Qiu-Ling FanDepartment of Nephrology, First Hospital of China Medical University, No. 155 Nanjing Bei Street, Shenyang 110001, People’s Republic of ChinaTel +86 13904012680Email cmufql@163.comBackground: 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
format	article
author	Wen S Wang ZH Zhang CX Yang Y Fan QL
author_facet	Wen S Wang ZH Zhang CX Yang Y Fan QL
author_sort	Wen S
title	Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis
title_short	Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis
title_full	Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis
title_fullStr	Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis
title_full_unstemmed	Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis
title_sort	caspase-3 promotes diabetic kidney disease through gasdermin e-mediated progression to secondary necrosis during apoptosis
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/8a2c8d8cdce442048352e44a66b7765e
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Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis

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