ArticleAmerican journal of physiology. Renal physiology2012
zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function.
Article in American journal of physiology. Renal physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 80 citations in OpenAlex.
- Article
- Acute kidney injury: pathogenesis and therapeutic interventions.Molecular biomedicine · 2025Review
- Cathepsin B induces kidney diseases through different types of programmed cell death.Frontiers in immunology · 2025Review
- Autophagy in Disease Onset and Progression.Aging and disease · 2024Review
- Cell death induced by acute renal injury: a perspective on the contributions of accidental and programmed cell death.American journal of physiology. Renal physiology · 2024Review
- Autophagy and mitophagy: physiological implications in kidney inflammation and diseases.American journal of physiology. Renal physiology · 2023Review
- Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential.Frontiers in pharmacology · 2023Review
- Gene Expression Analysis inInternational journal of molecular sciences · 2022Article
- The multifaceted role of kidney tubule mitochondrial dysfunction in kidney disease development.Trends in cell biology · 2022Review
- Nonapoptotic caspases in neural development and in anesthesia-induced neurotoxicity.Trends in neurosciences · 2022Review
- The pathological role of damaged organelles in renal tubular epithelial cells in the progression of acute kidney injury.Cell death discovery · 2022Review
- Protective effect of HMolecular medicine reports · 2022Article
- Involvement of Inflammasome Components in Kidney Disease.Antioxidants (Basel, Switzerland) · 2022Review
- A Balance Between Autophagy and Other Cell Death Modalities in Cancer.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Caspase Inhibition Affects the Expression of Autophagy-Related Molecules in Chondrocytes.Cartilage · 2021Article
- Review
- Lysosome Depletion-Triggered Autophagy Impairment in Progressive Kidney Injury.Kidney diseases (Basel, Switzerland) · 2021Review
- Lansoprazole promotes cisplatin-induced acute kidney injury via enhancing tubular necroptosis.Journal of cellular and molecular medicine · 2021Article
- HIF in Nephrotoxicity during Cisplatin Chemotherapy: Regulation, Function and Therapeutic Potential.Cancers · 2021Review
- Autophagy in kidney homeostasis and disease.Nature reviews. Nephrology · 2020Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Cisplatin injury to renal tubular epithelial cells (RTEC) is accompanied by autophagy and caspase activation. However, autophagy gradually decreases during the course of cisplatin injury. The role of autophagy and the mechanism of its decrease during cisplatin injury are not well understood. This study demonstrated that autophagy proteins beclin-1, Atg5, and Atg12 were cleaved and degraded during the course of cisplatin injury in RTEC and the kidney. zVAD-fmk, a widely used pancaspase inhibitor, blocked cleavage of autophagy proteins suggesting that zVAD-fmk would promote the autophagy pathway. Unexpectedly, zVAD-fmk blocked clearance of the autophagosomal cargo, indicating lysosomal dysfunction. zVAD-fmk markedly inhibited cisplatin-induced lysosomal cathepsin B and calpain activities and therefore impaired autophagic flux. In a mouse model of cisplatin nephrotoxicity, zVAD-fmk impaired autophagic flux by blocking autophagosomal clearance as revealed by accumulation of key autophagic substrates p62 and LC3-II. Furthermore, zVAD-fmk worsened cisplatin-induced renal dysfunction. Chloroquine, a lysomotropic agent that is known to impair autophagic flux, also exacerbated cisplatin-induced decline in renal function. These findings demonstrate that impaired autophagic flux induced by zVAD-fmk or a lysomotropic agent worsened renal function in cisplatin acute kidney injury (AKI) and support a protective role of autophagy in AKI. These studies also highlight that the widely used antiapoptotic agent zVAD-fmk may be contraindicated as a therapeutic agent for preserving renal function in AKI.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.