2. Academic Validation
  3. The hippo-YAP1/HIF-1α pathway mediates arsenic-induced renal fibrosis

The hippo-YAP1/HIF-1α pathway mediates arsenic-induced renal fibrosis

  • Environ Res. 2024 Jun 4:257:119325. doi: 10.1016/j.envres.2024.119325.
Wei Di 1,  Yan Li 2,  Lei Zhang 1,  Qing Zhou 1,  Zhushan Fu 1,  Shuhua Xi 3
Affiliations

Affiliations

  • 1 Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenicy, Shenyang, Liaoning, 110122, China; Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China.
  • 2 Institute of Foreign Languages, China Medical University, Shenyang, Liaoning, 110122, China.
  • 3 Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenicy, Shenyang, Liaoning, 110122, China; Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China. Electronic address: shxi@cmu.edu.cn.
PMID: 38844032 DOI: 10.1016/j.envres.2024.119325
Abstract

Epidemiological evidence reveals that arsenic increases the risk of chronic kidney disease (CKD) in humans, but its mechanism of action has so far been unclear. Fibrosis is the manifestation of end-stage renal disease. Hypoxia is recognized as a vital event accompanying the progression of renal fibrosis. KM mice were exposed to 0, 20, 40, and 80 mg/L NaAsO2 for 12 weeks. HK-2 cells were treated with 1 μM NaAsO2 for 4 weeks. The results showed that arsenic increased the expression of hypoxia-inducible factor 1α (HIF-1α) (P < 0.05), which is involved in inorganic arsenic-induced renal fibrosis. The Hippo signaling pathway is the upstream signal of HIF-1α and the kinase cascade of Large tumor suppressor kinase 1 (LATS1) and Yes-associated protein 1 (YAP1) is the heart of the Hippo pathway. Our results showed that protein expressions of LATS1 and phosphorylated YAP1 were decreased, and dephosphorylated YAP1 expression increased in arsenic-treated mouse kidneys and human HK-2 cells (P < 0.05). Our research manifested that arsenic treatment suppressed the Hippo signaling and induced high expression of YAP1 into the nucleus. We also found that YAP1 was involved in arsenic-induced renal fibrosis by forming a complex with HIF-1α and maintaining HIF-1α stability. Our findings indicate that YAP1 is a potential target for molecular-based therapy for arsenic-mediated renal fibrosis.

Keywords

Arsenic; CKD; Fibrosis; HIF-1α; YAP1.

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