Calcimimetic compound NPS R-467 protects against chronic cadmium-induced mouse kidney injury by restoring autophagy process

Jie Gu, Zhen Ren, Jinfeng Zhao, Frank Addai Peprah, Yimin Xie, Dongrui Cheng, Yanwei Wang, Haitao Liu, Chris K C WONG, Yang Zhou, Haifeng Shi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

In the kidney, disturbance of calcium homeostasis can cause renal hemodynamic changes, leading to glomerulonephritis, tubular damage and renal vascular disease, and thus promotes the development of chronic kidney disease (CKD). Cadmium (Cd) is a toxic heavy metals proved to induce disturbances of calcium homeostasis and nephrotoxicity. Calcium sensing receptor (CaSR) is abundantly expressed in the kidney and plays an important role in maintaining body calcium homeostasis. Our previous study suggested that the activation of CaSR could act as a protective pathway to reduce Cd-induced cytotoxicity in renal proximal tubular cells. However, its application in animal models, its treatment efficacy and underlying mechanisms are still unclear. Therefore, an in vivo animal model (ICR male mouse, n = 5) subjected to Cd-induced nephrotoxicity was used in this study. In the present study, the results indicated that long-term (4 weeks) but not short-term (7 days) Cd exposure induced kidney injury, including induced glomerular atrophy, renal proximal tubule damage, increased malondialdehyde (MDA) level, elevated urine protein quantity, and upregulated kidney injury molecule 1 (KIM-1). It was further observed that chronic Cd exposure induced inhibition of autophagy flux, which triggered kidney apoptosis and injury. However, NPS R-467 restored Cd-inhibited autophagy flux and reduced Cd-induced kidney apoptosis and injury. Finding from this study indicated that activation of CaSR in prevention from nephrotoxicity and kidney injury caused by Cd, which might be helpful for the treatment of clinical CKD.

Original languageEnglish
Article number110052
JournalEcotoxicology and Environmental Safety
Volume189
DOIs
Publication statusPublished - Feb 2020

Scopus Subject Areas

  • Pollution
  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

User-Defined Keywords

  • Apoptosis
  • Autophagy
  • Cadmium
  • CaSR
  • Kidney injury

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