The key role of proteostasis at mitochondria-associated endoplasmic reticulum membrane in vanadium-induced nephrotoxicity using a proteomic strategy

Excessive vanadium (V) contamination is an attracting growing concern, which can negatively affect the health of human and ecosystems. But how V causes nephrotoxicity and the role of mitochondria-associated endoplasmic reticulum membrane (MAM) in V-induced nephrotoxicity have remained elusive. To explore the detailed mechanism and screen of potential effective drugs for V-evoked nephrotoxicity, a total of 72 ducks were divided into two groups, control group and V group (30 mg/kg V). Results showed that excessive V damaged kidney function of ducks including causing histopathological abnormality, biochemical makers derangement and oxidative stress. Then MAM of duck kidneys was extracted to investigate differentially expressed proteins (DEPs) under V exposure using proteomics analysis. Around 4240 MAM-localized proteins were identified, of which 412 DEPs showed dramatic changes, including 335 upregulated and 77 downregulated DEPs. On the basis of gene ontology (GO), string and KEGG database analysis, excessive V led to nephrotoxicity primarily by affecting MAM-mediated metabolic pathways, especially elevating the endoplasmic Reticulum (ER) proteostasis related pathway. Further validation analysis of the detected genes and proteins of ER proteostasis related pathway under V poisoning revealed a consistent relationship with proteome analysis, indicating that V disrupted MAM-mediated ER proteostasis. Accordingly, our data proved the critical role for MAM in V-evoked nephrotoxicity, particularly with MAM-mediated ER proteostasis, providing promising insights into the toxicological exploration mechanisms of V.

Automated summary

Excessive vanadium contamination is a growing concern due to its negative effects on human health and ecosystems, particularly nephrotoxicity. The role of mitochondria-associated endoplasmic reticulum membrane (MAM) in vanadium-induced nephrotoxicity has been investigated. Proteomics analysis revealed that vanadium primarily affects MAM-mediated metabolic pathways, particularly the endoplasmic reticulum (ER) proteostasis pathway. These findings provide promising insights into the toxicological mechanisms of vanadium and the critical role of MAM.