ArticleJournal of diabetes investigation2022
VX-765 ameliorates renal injury and fibrosis in diabetes by regulating caspase-1-mediated pyroptosis and inflammation.
Article in Journal of diabetes investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 71 citations in OpenAlex.
- The mechanism and therapeutic prospect of HIF-1 α/BNIP3 pathway in regulating mitophagy in tubulointerstitial fibrosis.Renal failure · 2026Review
- Article
- Programmed cell death in kidney disease: integrated crosstalk among ferroptosis, pyroptosis, apoptosis, and cuproptosis.Apoptosis : an international journal on programmed cell death · 2026Review
- Endothelial cell-specific knockout of ATG5 ameliorates inflammation and renal fibrosis by regulating pyroptosis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Targeting pyroptosis in renal fibrosis: From molecular mechanisms to therapeutic horizons (Review).International journal of molecular medicine · 2026Review
- Small molecules targeting regulated cell death for chronic kidney disease therapy.Journal of pharmaceutical analysis · 2026Review
- Sublytic pyroptosis blocks Schwann cell remyelination through caspase-1-mediated Tyro3 cleavage.Journal of neuroinflammation · 2026Article
- Cell-Free DNA-Based Theranostics for Inflammatory Disorders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- The inflammation-pyroptosis axis links local and systemic biomarker profiles to active alveolar bone microstructural deterioration.Frontiers in physiology · 2026Article
- TRPC6 Inhibition Attenuates Renal Tubulointerstitial Fibrosis via the Reactive Oxygen Species/TXNIP/NLRP3 Signaling Pathway.Kidney & blood pressure research · 2026Article
- Crosstalk of regulated cell death pathways in sepsis-associated acute kidney injury: implications for therapy.Frontiers in cell and developmental biology · 2026Review
- Pyroptosis in premature ovarian insufficiency: pathogenic mechanisms, pathway crosstalk, and therapeutic strategies.Frontiers in medicine · 2026Review
- Cross-talk among novel programmed cell death pathways: a decisive network in renal ischemia-reperfusion injury.Frontiers in immunology · 2026Review
- Tubular injury in diabetic kidney disease: a focus on regulated cell death.Frontiers in endocrinology · 2026Review
- Mechanism of RBM15 in high glucose-induced pyroptosis of renal tubular epithelial cells.Clinical and experimental nephrology · 2025Article
- Diagnostic PANoptosis-related genes in acute kidney injury: bioinformatics, machine learning, and validation.Annals of medicine · 2025Article
- The Inflammatory Cell Death in Diabetic Kidney Disease: Integrating Multifactorial Mechanisms into Novel Therapeutics.International journal of molecular sciences · 2025Review
- Bioinformatics and experimental animal model reveal the prognostic value of immunogenic cell death-related proteins in idiopathic pulmonary fibrosis.Journal of thoracic disease · 2025Article
- Targeting pyroptosis in myocardial inflammation and fibrosis: molecular mechanisms and therapeutic strategies.Apoptosis : an international journal on programmed cell death · 2025Review
- The Regulatory Role of NcRNAs in Pyroptosis and Disease Pathogenesis.Cell biochemistry and biophysics · 2025Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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