VX‐765 ameliorates renal injury and fibrosis in diabetes by regulating caspase‐1‐mediated pyroptosis and inflammation

Introduction As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX‐765 is a safe and effective inhibitor of caspase‐1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but i...

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Published inJournal of diabetes investigation Vol. 13; no. 1; pp. 22 - 33
Main Authors Wen, Si, Deng, Fei, Li, Lulu, Xu, Li, Li, Xin, Fan, Qiuling
Format Journal Article
LanguageEnglish
Published Japan John Wiley & Sons, Inc 01.01.2022
John Wiley and Sons Inc
Wiley
Subjects
Animals
Antibodies
Antigens
Apoptosis
Balloon treatment
Caspase
Caspase 1 - metabolism
Caspase‐1
CD45 antigen
Cell culture
Cell Culture Techniques
Cell death
Cell membranes
Collagen (type I)
Creatinine
Cytotoxicity
Dehydrogenases
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - pathology
Diabetic Nephropathies - drug therapy
Diabetic Nephropathies - pathology
Diabetic nephropathy
Dipeptides - pharmacology
Enzyme-linked immunosorbent assay
Epilepsy
Fibronectin
Fibrosis
Flow cytometry
Glucose
Glucose - pharmacology
GSDMD
Humans
Immunoprecipitation
Immunoreactivity
Inflammation
Kidney - pathology
Kidney Tubules - drug effects
Kidney Tubules - pathology
Laboratory animals
Male
Mice
Microscopy
Nephropathy
Original
para-Aminobenzoates - pharmacology
Pyroptosis
Pyroptosis - drug effects
Renal cortex
Renal function
Urine
VX‐765
United States > US
China
GSDMD
Diabetic nephropathy
Inflammation
Pyroptosis
VX-765
Caspase-1
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Abstract Introduction As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX‐765 is a safe and effective inhibitor of caspase‐1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but its application in DN is still undefined. Materials and Methods Immunoblot, co‐immunoprecipitation, confocal microscope and flow cytometry were used to analyze the effects of glucose on pyroptosis in renal tubular epithelia (HK‐2). In vitro, selective caspase‐1 inhibitors VX‐765 and Z‐YVAD‐FMK were administered. Pyroptosis and fibrogenesis were determined by immunoblot, ELISA, cytotoxicity assay and flow cytometry. In vivo, diabetic mice were administered with 100 mg/kg VX‐765. Renal function, pathological changes, and the expressions of NLRC4, GSDMD, IL‐1β, collagen I, fibronectin and CD45 in renal cortex were evaluated. Results We identified NLRC4 as a sensor for caspase‐1 activation. Moreover, we provided morphological and molecular evidence for pyroptosis in glucose‐stressed tubular cells, including ballooned cell membrane, caspase‐1 immunoreactivity, GSDMD cleavage, and the release of inflammatory cytokine and cellular contents. All these effects were prevented by treatment with VX‐765 or Z‐YVAD‐FMK, confirming that caspase‐1 effectively regulates the occurrence of pyroptosis in HK‐2 cells. In vivo, treatment of diabetic animals with VX‐765 ameliorated renal function, suppressed inflammatory cell infiltration and pyroptosis‐associated protein expression, and mitigated tubulointerstitial fibrosis. Conclusions This work revealed that caspase‐1‐mediated pyroptosis drives renal inflammation and fibrosis in diabetes. Our results are the first demonstration of VX‐765 representing a promising therapeutic opportunity for alleviating the progression of DN. VX‐765 represents a promising therapeutic opportunity for alleviating the progression of diabetic nephropathy via inhibiting caspase‐1‐mediated pyroptosis, renal inflammation and fibrosis.
AbstractList As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX-765 is a safe and effective inhibitor of caspase-1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but its application in DN is still undefined.INTRODUCTIONAs a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX-765 is a safe and effective inhibitor of caspase-1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but its application in DN is still undefined.Immunoblot, co-immunoprecipitation, confocal microscope and flow cytometry were used to analyze the effects of glucose on pyroptosis in renal tubular epithelia (HK-2). In vitro, selective caspase-1 inhibitors VX-765 and Z-YVAD-FMK were administered. Pyroptosis and fibrogenesis were determined by immunoblot, ELISA, cytotoxicity assay and flow cytometry. In vivo, diabetic mice were administered with 100 mg/kg VX-765. Renal function, pathological changes, and the expressions of NLRC4, GSDMD, IL-1β, collagen I, fibronectin and CD45 in renal cortex were evaluated.MATERIALS AND METHODSImmunoblot, co-immunoprecipitation, confocal microscope and flow cytometry were used to analyze the effects of glucose on pyroptosis in renal tubular epithelia (HK-2). In vitro, selective caspase-1 inhibitors VX-765 and Z-YVAD-FMK were administered. Pyroptosis and fibrogenesis were determined by immunoblot, ELISA, cytotoxicity assay and flow cytometry. In vivo, diabetic mice were administered with 100 mg/kg VX-765. Renal function, pathological changes, and the expressions of NLRC4, GSDMD, IL-1β, collagen I, fibronectin and CD45 in renal cortex were evaluated.We identified NLRC4 as a sensor for caspase-1 activation. Moreover, we provided morphological and molecular evidence for pyroptosis in glucose-stressed tubular cells, including ballooned cell membrane, caspase-1 immunoreactivity, GSDMD cleavage, and the release of inflammatory cytokine and cellular contents. All these effects were prevented by treatment with VX-765 or Z-YVAD-FMK, confirming that caspase-1 effectively regulates the occurrence of pyroptosis in HK-2 cells. In vivo, treatment of diabetic animals with VX-765 ameliorated renal function, suppressed inflammatory cell infiltration and pyroptosis-associated protein expression, and mitigated tubulointerstitial fibrosis.RESULTSWe identified NLRC4 as a sensor for caspase-1 activation. Moreover, we provided morphological and molecular evidence for pyroptosis in glucose-stressed tubular cells, including ballooned cell membrane, caspase-1 immunoreactivity, GSDMD cleavage, and the release of inflammatory cytokine and cellular contents. All these effects were prevented by treatment with VX-765 or Z-YVAD-FMK, confirming that caspase-1 effectively regulates the occurrence of pyroptosis in HK-2 cells. In vivo, treatment of diabetic animals with VX-765 ameliorated renal function, suppressed inflammatory cell infiltration and pyroptosis-associated protein expression, and mitigated tubulointerstitial fibrosis.This work revealed that caspase-1-mediated pyroptosis drives renal inflammation and fibrosis in diabetes. Our results are the first demonstration of VX-765 representing a promising therapeutic opportunity for alleviating the progression of DN.CONCLUSIONSThis work revealed that caspase-1-mediated pyroptosis drives renal inflammation and fibrosis in diabetes. Our results are the first demonstration of VX-765 representing a promising therapeutic opportunity for alleviating the progression of DN.
Introduction As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX‐765 is a safe and effective inhibitor of caspase‐1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but its application in DN is still undefined. Materials and Methods Immunoblot, co‐immunoprecipitation, confocal microscope and flow cytometry were used to analyze the effects of glucose on pyroptosis in renal tubular epithelia (HK‐2). In vitro, selective caspase‐1 inhibitors VX‐765 and Z‐YVAD‐FMK were administered. Pyroptosis and fibrogenesis were determined by immunoblot, ELISA, cytotoxicity assay and flow cytometry. In vivo, diabetic mice were administered with 100 mg/kg VX‐765. Renal function, pathological changes, and the expressions of NLRC4, GSDMD, IL‐1β, collagen I, fibronectin and CD45 in renal cortex were evaluated. Results We identified NLRC4 as a sensor for caspase‐1 activation. Moreover, we provided morphological and molecular evidence for pyroptosis in glucose‐stressed tubular cells, including ballooned cell membrane, caspase‐1 immunoreactivity, GSDMD cleavage, and the release of inflammatory cytokine and cellular contents. All these effects were prevented by treatment with VX‐765 or Z‐YVAD‐FMK, confirming that caspase‐1 effectively regulates the occurrence of pyroptosis in HK‐2 cells. In vivo, treatment of diabetic animals with VX‐765 ameliorated renal function, suppressed inflammatory cell infiltration and pyroptosis‐associated protein expression, and mitigated tubulointerstitial fibrosis. Conclusions This work revealed that caspase‐1‐mediated pyroptosis drives renal inflammation and fibrosis in diabetes. Our results are the first demonstration of VX‐765 representing a promising therapeutic opportunity for alleviating the progression of DN. VX‐765 represents a promising therapeutic opportunity for alleviating the progression of diabetic nephropathy via inhibiting caspase‐1‐mediated pyroptosis, renal inflammation and fibrosis.
Abstract Introduction As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX‐765 is a safe and effective inhibitor of caspase‐1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but its application in DN is still undefined. Materials and Methods Immunoblot, co‐immunoprecipitation, confocal microscope and flow cytometry were used to analyze the effects of glucose on pyroptosis in renal tubular epithelia (HK‐2). In vitro, selective caspase‐1 inhibitors VX‐765 and Z‐YVAD‐FMK were administered. Pyroptosis and fibrogenesis were determined by immunoblot, ELISA, cytotoxicity assay and flow cytometry. In vivo, diabetic mice were administered with 100 mg/kg VX‐765. Renal function, pathological changes, and the expressions of NLRC4, GSDMD, IL‐1β, collagen I, fibronectin and CD45 in renal cortex were evaluated. Results We identified NLRC4 as a sensor for caspase‐1 activation. Moreover, we provided morphological and molecular evidence for pyroptosis in glucose‐stressed tubular cells, including ballooned cell membrane, caspase‐1 immunoreactivity, GSDMD cleavage, and the release of inflammatory cytokine and cellular contents. All these effects were prevented by treatment with VX‐765 or Z‐YVAD‐FMK, confirming that caspase‐1 effectively regulates the occurrence of pyroptosis in HK‐2 cells. In vivo, treatment of diabetic animals with VX‐765 ameliorated renal function, suppressed inflammatory cell infiltration and pyroptosis‐associated protein expression, and mitigated tubulointerstitial fibrosis. Conclusions This work revealed that caspase‐1‐mediated pyroptosis drives renal inflammation and fibrosis in diabetes. Our results are the first demonstration of VX‐765 representing a promising therapeutic opportunity for alleviating the progression of DN.
As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX-765 is a safe and effective inhibitor of caspase-1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but its application in DN is still undefined. Immunoblot, co-immunoprecipitation, confocal microscope and flow cytometry were used to analyze the effects of glucose on pyroptosis in renal tubular epithelia (HK-2). In vitro, selective caspase-1 inhibitors VX-765 and Z-YVAD-FMK were administered. Pyroptosis and fibrogenesis were determined by immunoblot, ELISA, cytotoxicity assay and flow cytometry. In vivo, diabetic mice were administered with 100 mg/kg VX-765. Renal function, pathological changes, and the expressions of NLRC4, GSDMD, IL-1β, collagen I, fibronectin and CD45 in renal cortex were evaluated. We identified NLRC4 as a sensor for caspase-1 activation. Moreover, we provided morphological and molecular evidence for pyroptosis in glucose-stressed tubular cells, including ballooned cell membrane, caspase-1 immunoreactivity, GSDMD cleavage, and the release of inflammatory cytokine and cellular contents. All these effects were prevented by treatment with VX-765 or Z-YVAD-FMK, confirming that caspase-1 effectively regulates the occurrence of pyroptosis in HK-2 cells. In vivo, treatment of diabetic animals with VX-765 ameliorated renal function, suppressed inflammatory cell infiltration and pyroptosis-associated protein expression, and mitigated tubulointerstitial fibrosis. This work revealed that caspase-1-mediated pyroptosis drives renal inflammation and fibrosis in diabetes. Our results are the first demonstration of VX-765 representing a promising therapeutic opportunity for alleviating the progression of DN.
VX‐765 represents a promising therapeutic opportunity for alleviating the progression of diabetic nephropathy via inhibiting caspase‐1‐mediated pyroptosis, renal inflammation and fibrosis.
IntroductionAs a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX‐765 is a safe and effective inhibitor of caspase‐1, that was well tolerated in a phase II clinical trial in patients with epilepsy, but its application in DN is still undefined.Materials and MethodsImmunoblot, co‐immunoprecipitation, confocal microscope and flow cytometry were used to analyze the effects of glucose on pyroptosis in renal tubular epithelia (HK‐2). In vitro, selective caspase‐1 inhibitors VX‐765 and Z‐YVAD‐FMK were administered. Pyroptosis and fibrogenesis were determined by immunoblot, ELISA, cytotoxicity assay and flow cytometry. In vivo, diabetic mice were administered with 100 mg/kg VX‐765. Renal function, pathological changes, and the expressions of NLRC4, GSDMD, IL‐1β, collagen I, fibronectin and CD45 in renal cortex were evaluated.ResultsWe identified NLRC4 as a sensor for caspase‐1 activation. Moreover, we provided morphological and molecular evidence for pyroptosis in glucose‐stressed tubular cells, including ballooned cell membrane, caspase‐1 immunoreactivity, GSDMD cleavage, and the release of inflammatory cytokine and cellular contents. All these effects were prevented by treatment with VX‐765 or Z‐YVAD‐FMK, confirming that caspase‐1 effectively regulates the occurrence of pyroptosis in HK‐2 cells. In vivo, treatment of diabetic animals with VX‐765 ameliorated renal function, suppressed inflammatory cell infiltration and pyroptosis‐associated protein expression, and mitigated tubulointerstitial fibrosis.ConclusionsThis work revealed that caspase‐1‐mediated pyroptosis drives renal inflammation and fibrosis in diabetes. Our results are the first demonstration of VX‐765 representing a promising therapeutic opportunity for alleviating the progression of DN.
Author Wen, Si
Xu, Li
Deng, Fei
Li, Xin
Li, Lulu
Fan, Qiuling
AuthorAffiliation 3 Department of Urology Second Xiangya Hospital of Central South University Changsha China
4 Department of Laboratory Medicine First Hospital of China Medical University Shenyang China
2 Department of Nephrology First Affiliated Hospital of Dalian Medical University Dalian China
1 Department of Nephrology First Hospital of China Medical University Shenyang China
AuthorAffiliation_xml – name: 3 Department of Urology Second Xiangya Hospital of Central South University Changsha China
– name: 4 Department of Laboratory Medicine First Hospital of China Medical University Shenyang China
– name: 1 Department of Nephrology First Hospital of China Medical University Shenyang China
– name: 2 Department of Nephrology First Affiliated Hospital of Dalian Medical University Dalian China
Author_xml – sequence: 1
  givenname: Si
  orcidid: 0000-0002-9850-0702
  surname: Wen
  fullname: Wen, Si
  organization: First Affiliated Hospital of Dalian Medical University
– sequence: 2
  givenname: Fei
  surname: Deng
  fullname: Deng, Fei
  organization: Second Xiangya Hospital of Central South University
– sequence: 3
  givenname: Lulu
  surname: Li
  fullname: Li, Lulu
  organization: First Hospital of China Medical University
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  orcidid: 0000-0001-8925-7192
  surname: Xu
  fullname: Xu, Li
  organization: First Hospital of China Medical University
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  givenname: Xin
  surname: Li
  fullname: Li, Xin
  organization: First Hospital of China Medical University
– sequence: 6
  givenname: Qiuling
  surname: Fan
  fullname: Fan, Qiuling
  email: cmufql@163.com
  organization: First Hospital of China Medical University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/34494385$$D View this record in MEDLINE/PubMed
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Issue 1
Keywords GSDMD
Diabetic nephropathy
Inflammation
Pyroptosis
VX-765
Caspase-1
Language English
License Attribution-NonCommercial
2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.
This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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Snippet Introduction As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN)....
As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN). VX-765 is a...
IntroductionAs a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic nephropathy (DN)....
VX‐765 represents a promising therapeutic opportunity for alleviating the progression of diabetic nephropathy via inhibiting caspase‐1‐mediated pyroptosis,...
Abstract Introduction As a lytic inflammatory cell death, pyroptosis has been recently described but has not been unequivocally elucidated in diabetic...
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StartPage 22
SubjectTerms Animals
Antibodies
Antigens
Apoptosis
Balloon treatment
Caspase
Caspase 1 - metabolism
Caspase‐1
CD45 antigen
Cell culture
Cell Culture Techniques
Cell death
Cell membranes
Collagen (type I)
Creatinine
Cytotoxicity
Dehydrogenases
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - pathology
Diabetic Nephropathies - drug therapy
Diabetic Nephropathies - pathology
Diabetic nephropathy
Dipeptides - pharmacology
Enzyme-linked immunosorbent assay
Epilepsy
Fibronectin
Fibrosis
Flow cytometry
Glucose
Glucose - pharmacology
GSDMD
Humans
Immunoprecipitation
Immunoreactivity
Inflammation
Kidney - pathology
Kidney Tubules - drug effects
Kidney Tubules - pathology
Laboratory animals
Male
Mice
Microscopy
Nephropathy
Original
para-Aminobenzoates - pharmacology
Pyroptosis
Pyroptosis - drug effects
Renal cortex
Renal function
Urine
VX‐765
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  providerName: Wiley-Blackwell
Title VX‐765 ameliorates renal injury and fibrosis in diabetes by regulating caspase‐1‐mediated pyroptosis and inflammation
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fjdi.13660
https://www.ncbi.nlm.nih.gov/pubmed/34494385
https://www.proquest.com/docview/2619098938
https://www.proquest.com/docview/2570375530
https://pubmed.ncbi.nlm.nih.gov/PMC8756311
https://doaj.org/article/2136e0e461e441b3895fbf09b59e9bdf
Volume 13
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