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

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.

Inhibition of Autophagy Alleviates Cadmium-Induced Mouse Spleen and Human B Cells Apoptosis.

Cadmium (Cd) is a toxic heavy metal that can accumulate and cause severe damage to many organs, such as liver, kidney, lung, etc. Cd also significantly suppresses immunity, however, the underlying mechanism involved in Cd-induced immunnotoxicity is still unclear. The present study indicated that semichronic Cd exposure (7 days) induced apoptotic damage of mouse spleen. In human Ramos B cells, Cd exposure also induced apoptosis, which was dependent on Cd-induced vacuole membrane protein 1 (VMP1) expression and autophagy. Cd-induced autophagy and apoptosis were abated when VMP1 expression was knockdown. In addition, Cd-induced VMP1 expression, autophagy, and apoptosis were dependent on the elevation of Ca2+ and reactive oxygen species (ROS). More important, Cd exposure also induced VMP1 expression and autophagy in mouse spleen tissue, and the intraperitoneal injection of the autophagy inhibitor chloroquine (CQ) into mice effectively reduced Cd-induced spleen apoptotic damage. Taken together, these results indicate Cd-induced autophagy, promotes apoptosis in immune cells, and inhibition of autophagy can alleviate Cd-induced spleen and immune cell apoptosis. This study might provide the groundwork for future studies on Cd-induced immunomodulatory effects and immune diseases.

Fatty liver disease induced by perfluorooctane sulfonate: Novel insight from transcriptome analysis.

Perfluorooctane sulfonate (PFOS), a hepato-toxicant and potential non-genotoxic carcinogen, was widely used in industrial and commercial products. Recent studies have revealed the ubiquitous occurrence of PFOS in the environment and in humans worldwide. The widespread contamination of PFOS in human serum raised concerns about its long-term toxic effects and its potential risks to human health. Using fatty liver mutant foie gras (fgr(-/-))/transport protein particle complex 11 (trappc11(-/-)) and PFOS-exposed wild-type zebrafish embryos as the study model, together with RNA sequencing and comparative transcriptomic analysis, we identified 499 and 1414 differential expressed genes (DEGs) in PFOS-exposed wild-type and trappc11 mutant zebrafish, respectively. Also, the gene ontology analysis on common deregulated genes was found to be associated with different metabolic processes such as the carbohydrate metabolic process, glycerol ether metabolic process, mannose biosynthetic process, de novo' (Guanosine diphosphate) GDP-l-fucose biosynthetic process, GDP-mannose metabolic process and galactose metabolic process. Ingenuity Pathway Analysis further highlighted that these deregulated gene clusters are closely related to hepatitis, inflammation, fibrosis and cirrhosis of liver cells, suggesting that PFOS can cause liver pathogenesis and non-alcoholic fatty liver disease in zebrafish. The transcriptomic alterations revealed may serve as biomarkers for the hepatotoxic effect of PFOS.