1. TRPA1 protects against contrast-induced renal tubular injury by preserving mitochondrial dynamics via the AMPK/DRP1 pathway.
- Author
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Wang, Xinquan, Luo, Tao, Yang, Yi, Yang, Lun, Liu, Min, Zou, Qingliang, Wang, Dan, Yang, Changqiang, Xue, Qiang, Liu, Sen, Wan, Jindong, He, Gaomin, Zeng, Anping, Hou, Jixin, Ma, Shuangtao, and Wang, Peijian
- 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. [Display omitted] • TRPA1 is functionally expressed in renal proximal tubular cells. • Activation or overexpression of TRPA1 in renal proximal tubule ameliorates CI-AKI. • The renal protective effects of TRPA1 are due to improved mitochondrial function. • TRPA1 inhibits mitochondrial fission and oxidative stress and enhances mitophagy. • TRPA1 improves mitochondrial function via the AMPK/DRP1 pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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