{"title":"TRPA1 protects against contrast-induced renal tubular injury by preserving mitochondrial dynamics via the AMPK/DRP1 pathway","authors":"","doi":"10.1016/j.freeradbiomed.2024.09.012","DOIUrl":null,"url":null,"abstract":"<div><p>Mitochondrial dysfunction and oxidative stress are involved in the development of contrast-induced acute kidney injury (CI-AKI). The present study aimed to reveal the role of transient receptor potential ankyrin 1 (TRPA1), an oxidative sensor, in CI-AKI. Trpa1<sup>PT−/−</sup> mice with Trpa1 conditionally knocked out in renal proximal tubular (PT) cells, Trpa1 overexpression mice (Trpa1-OE), and TRPA1 agonists and antagonists were used to study its function in a mouse model of iohexol-induced CI-AKI. We found that TRPA1 was functionally expressed in PT cells. Activation of TRPA1 with cinnamaldehyde or overexpression of Trpa1 remarkably ameliorated renal tubular injury and dysfunction in a mouse model of CI-AKI, while CI-AKI was significantly exacerbated in Trpa1<sup>PT−/−</sup> mice. Proteomics demonstrated that mouse kidneys with CI-AKI had downregulated proteins involved in mitochondrial dynamics and upregulated mitophagy-associated proteins. The beneficial effects of TRPA1 activation/overexpression on CI-AKI were associated with improved mitochondrial function, decreased mitochondrial fission and oxidative stress, enhanced mitophagy, and less apoptosis of renal tubular cells. TRPA1-induced decreases in mitochondrial fission were linked to upregulated fusion-related proteins (mitofusin 1, mitofusin 2 and optic atrophy 1) and downregulated fission mediator, phosphorylated dynamin-related protein 1 (Drp1). Importantly, inhibition of Drp1 with mitochondrial division inhibitor 1 improved CI-AKI. In addition, the decreased mitochondrial fission was also mediated by inactivation of AMP-activated protein kinase which mediates mitochondrial biogenesis. The findings suggest that TRPA1 plays a protective role in CI-AKI through regulating mitochondrial fission/fusion, biogenesis, and dysfunction. Activating TRPA1 may become novel therapeutic strategies for the prevention of CI-AKI.</p></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Biology and Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0891584924006592","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Mitochondrial dysfunction and oxidative stress are involved in the development of contrast-induced acute kidney injury (CI-AKI). The present study aimed to reveal the role of transient receptor potential ankyrin 1 (TRPA1), an oxidative sensor, in CI-AKI. Trpa1PT−/− mice with Trpa1 conditionally knocked out in renal proximal tubular (PT) cells, Trpa1 overexpression mice (Trpa1-OE), and TRPA1 agonists and antagonists were used to study its function in a mouse model of iohexol-induced CI-AKI. We found that TRPA1 was functionally expressed in PT cells. Activation of TRPA1 with cinnamaldehyde or overexpression of Trpa1 remarkably ameliorated renal tubular injury and dysfunction in a mouse model of CI-AKI, while CI-AKI was significantly exacerbated in Trpa1PT−/− mice. Proteomics demonstrated that mouse kidneys with CI-AKI had downregulated proteins involved in mitochondrial dynamics and upregulated mitophagy-associated proteins. The beneficial effects of TRPA1 activation/overexpression on CI-AKI were associated with improved mitochondrial function, decreased mitochondrial fission and oxidative stress, enhanced mitophagy, and less apoptosis of renal tubular cells. TRPA1-induced decreases in mitochondrial fission were linked to upregulated fusion-related proteins (mitofusin 1, mitofusin 2 and optic atrophy 1) and downregulated fission mediator, phosphorylated dynamin-related protein 1 (Drp1). Importantly, inhibition of Drp1 with mitochondrial division inhibitor 1 improved CI-AKI. In addition, the decreased mitochondrial fission was also mediated by inactivation of AMP-activated protein kinase which mediates mitochondrial biogenesis. The findings suggest that TRPA1 plays a protective role in CI-AKI through regulating mitochondrial fission/fusion, biogenesis, and dysfunction. Activating TRPA1 may become novel therapeutic strategies for the prevention of CI-AKI.
期刊介绍:
Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.