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Pharmacological Inhibition of Caspase-1 Ameliorates Cisplatin-Induced Nephrotoxicity through Suppression of Apoptosis, Oxidative Stress, and Inflammation in Mice
Caspase-1 is a proinflammatory caspase responsible for the proteolytic conversion of the precursor forms of interleukin-1β to its active form and plays an important role in the pathogenesis of various inflammatory diseases. It was reported that genetic deficiency of caspase-1 prevented cisplatin-ind...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323438/ https://www.ncbi.nlm.nih.gov/pubmed/30670928 http://dx.doi.org/10.1155/2018/6571676 |
Sumario: | Caspase-1 is a proinflammatory caspase responsible for the proteolytic conversion of the precursor forms of interleukin-1β to its active form and plays an important role in the pathogenesis of various inflammatory diseases. It was reported that genetic deficiency of caspase-1 prevented cisplatin-induced nephrotoxicity. However, whether pharmacological inhibition of caspase-1 also has a preventive effect against cisplatin-induced kidney injury has not been evaluated. In this study, we examined the effect of Ac-YVAD-cmk, a potent caspase-1-specific inhibitor, on renal function and histology in cisplatin-treated mice and explored its underlying mechanisms. We found that administration of Ac-YVAD-cmk effectively attenuated cisplatin-induced renal dysfunction, as evidenced by reduced plasma levels of blood urea nitrogen and creatinine, and histological abnormalities, such as tubular cell death, dilatation, and cast formation. Administration of Ac-YVAD-cmk inhibited caspase-3 activation as well as caspase-1 activation and attenuated apoptotic cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, in the kidneys of cisplatin-treated mice. Cisplatin-induced G2/M arrest of renal tubular cells was also reduced by caspase-1 inhibition. In addition, administration of Ac-YVAD-cmk reversed increased oxidative stress and depleted antioxidant capacity after cisplatin treatment. Moreover, increased macrophage accumulation and elevated expression of cytokines and chemokines were attenuated by caspase-1 inhibition. Taken together, these results suggest that caspase-1 inhibition by Ac-YVAD-cmk protects against cisplatin-induced nephrotoxicity through inhibition of renal tubular cell apoptosis, oxidative stress, and inflammatory responses. Our findings support the idea that caspase-1 may be a promising pharmacological target for the prevention of cisplatin-induced kidney injury. |
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