Contribution of Organ Vasculature in Rat Renal Analysis for Ochratoxin A: Relevance to Toxicology of Nephrotoxins

Abstract

Assumptions surrounding the kidney as a target for accumulation of ochratoxin A (OTA) are addressed because the contribution of the toxin in blood seems invariably to have been ignored. Adult rats were maintained for several weeks on toxin-contaminated feed. Using standard perfusion techniques, animals were anaesthetised, a blood sample was taken, one kidney was ligated, and the other kidney perfused with physiological saline in situ under normal blood pressure. Comparative analysis of OTA in pairs of kidneys showed marked reduction in the perfused organ in the range 37%–98% (mean 75%), demonstrating the general efficiency of perfusion supported also by histology, and implying a major role of blood in the total OTA content of kidney. Translation of OTA values in plasma to whole blood, and its predicted contribution as a 25% vascular compartment in kidney gave values similar to those in non-perfused kidneys. Thus, apparent ‘accumulation’ of OTA in kidney is due to binding to plasma proteins and long half-life in plasma. Attention should be re-focused on whole animal pharmacokinetics during chronic OTA exposure. Similar principles may be applied to DNA-OTA adducts which are now recognised as occurring in blood; application could also extend to other nephrotoxins such as aristolochic acid. Thus, at least, quantitative reassessment in urological tissues seems necessary in attributing adducts specifically as markers of potentially-tumourigenic exposure.

Protective Effect of Astaxanthin on Ochratoxin A-Induced Kidney Injury to Mice by Regulating Oxidative Stress-Related NRF2/KEAP1 Pathway

“…These results indicated that the mice in the OTA group had been poisoned. This deduction was confirmed using H&E staining, electron microscopy, and TUNEL staining, which were consistent with previous reports [40,41]. In addition, we found non-significant variations in CRE levels across all the groups…”

“…These results indicated that the mice in the OTA group had been poisoned. This deduction was confirmed using H&E staining, electron microscopy, and TUNEL staining, which were consistent with previous reports [40,41]. In addition, we found non-significant variations in CRE levels across all the groups due to the fact that OTA mainly affects the renal tubular reabsorption function, but has little effect on glomerular filtration function, and further research is needed to confirm this [42].…”

Ochratoxin A mediates MAPK activation, modulates <i>IL-2</i> and <i>TNF-α</i> mRNA expression and induces apoptosis by mitochondria-dependent and mitochondria-independent pathways in human H9 T cells

“…Generally, in vitro treatment with relatively high OTA doses provides similar effects to those observed in vivo after chronic low doses exposure, especially in case of DNA-adducts caused by OTA (Pfohl-Leszkowicz and Castegnaro, 2005;Mantle et al, 2015), recent studies carried on human peripheral blood lymphocytes, showed a viability decrease of 20-30% following incubation with OTA concentrations less than 20 μM, (Gonzàlez-Arias et al, 2014;Ali et al, 2011). In the light of these data we have investigated cytotoxicity of OTA on H9 cells with concentrations up to 20 μM, to evaluate the sensibility of and TNF-α (B) mRNA levels were analyzed by real-time PCR using specific primers.…”

Ochratoxin A: Molecular Interactions, Mechanisms of Toxicity and Prevention at the Molecular Level

“…A previous study with albumin-deficient rats showed the very high importance of albumin binding regarding the slow elimination of OTA [ 29 ]. Furthermore, a recent study with rats also proved that the accumulation of OTA in the kidney is due to strong binding of OTA to plasma proteins and its long half-life in plasma [ 255 ]. It is very likely that, in humans, this impact could be more dominant because of the substantially stronger interaction of OTA with human albumin.…”