2. Academic Validation
  3. TRPA1 protects against contrast-induced renal tubular injury by preserving mitochondrial dynamics via the AMPK/DRP1 pathway

TRPA1 protects against contrast-induced renal tubular injury by preserving mitochondrial dynamics via the AMPK/DRP1 pathway

  • Free Radic Biol Med. 2024 Sep 13:224:521-539. doi: 10.1016/j.freeradbiomed.2024.09.012.
Xinquan Wang 1,  Tao Luo 1,  Yi Yang 1,  Lun Yang 1,  Min Liu 1,  Qingliang Zou 1,  Dan Wang 1,  Changqiang Yang 1,  Qiang Xue 2,  Sen Liu 1,  Jindong Wan 1,  Gaomin He 1,  Anping Zeng 1,  Jixin Hou 1,  Shuangtao Ma 3,  Peijian Wang 4
Affiliations

Affiliations

  • 1 Department of Cardiology, Department of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, China; Key Laboratory of Aging and Vascular Homeostasis at Chengdu Medical College of Sichuan Province, Chengdu, Sichuan, 610500, China; Clinical Research Center for Geriatrics of Sichuan Province, Chengdu, Sichuan, 610500, China.
  • 2 Department of Cardiology, Yanan Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, 650051, China.
  • 3 Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, 48824, USA. Electronic address: mashuang@msu.edu.
  • 4 Department of Cardiology, Department of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, China; Key Laboratory of Aging and Vascular Homeostasis at Chengdu Medical College of Sichuan Province, Chengdu, Sichuan, 610500, China; Clinical Research Center for Geriatrics of Sichuan Province, Chengdu, Sichuan, 610500, China. Electronic address: 23772194@qq.com.
PMID: 39278575 DOI: 10.1016/j.freeradbiomed.2024.09.012
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.

Keywords

Acute kidney injury; Contrast medium; Contrast-induced nephropathy; Drp1; TRPA1.

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