Evaluation of toxicological mechanisms of ochratoxin-A in human primary proximal tubule epithelial cells

Ochratoxin-A (OTA) is a ubiquitous mycotoxin contaminant in food products and a known nephrotoxin that is not currently regulated in the United States. OTA is hypothesized to be a potential environmental agent causing chronic kidney disease of unknown etiology (CKDu), however the mechanism of OTA toxicity in the human kidney remains elusive. This study aims to elucidate OTA-induced molecular toxicological pathways using primary human proximal tubule epithelial cells (PTECs). We demonstrated that exposure to OTA (10 μM) induces over 7000 differentially expressed genes, including key regulators of mitochondrial fission and fusion. This was confirmed at the cellular level by confocal microscopy, where a breakdown of the mitochondrial network was observed at 100 nM OTA. Crucially, OTA was found to significantly inhibit basal mitochondrial oxidative phosphorylation as well as glycolysis, indicating reduced bioenergetics and mitochondrial toxicity. In conclusion, we demonstrate that OTA induces mitochondrial dysfunction and reduced ATP production, leading to a senescent-like state in PTECs characteristic of renal disease progression. These findings provide insight into early toxicological endpoints induced by OTA which have been established as pathophysiological changes involved in chronic kidney disease.