The Impact of the Nephrotoxin Ochratoxin A on Human Renal Cells Studied by a Novel Co-Culture Model Is Influenced by the Presence of Fibroblasts

Abstract

The kidney is threatened by a lot of potentially toxic substances. To study the influence of the nephrotoxin ochratoxin A (OTA) we established a cell co-culture model consisting of human renal proximal tubule cells and fibroblasts. We studied the effect of OTA on cell survival, the expression of genes and/or proteins related to cell death, extracellular matrix and energy homeostasis. OTA-induced necrosis was enhanced in both cell types in the presence of the respective other cell type, whereas OTA-induced apoptosis was independent therefrom. In fibroblasts, but not in tubule cells, a co-culture effect was visible concerning the expression of the cell-cycle-related protein p21. The expression of the epithelial-to-mesenchymal transition-indicating protein vimentin was independent from the culture-condition. The expression of the OTA-induced lncRNA WISP1-AS1 was enhanced in co-culture. OTA exposure led to alterations in the expression of genes related to energy metabolism with a glucose-mobilizing effect and a reduced expression of mitochondrial proteins. Together we demonstrate that the reaction of cells can be different in the presence of cells which naturally are close-by, thus enabling a cellular cross-talk. Therefore, to evaluate the toxicity of a substance, it would be an advantage to consider the use of co-cultures instead of mono-cultures.

The Neurotoxic Effect of Ochratoxin-A on the Hippocampal Neurogenic Niche of Adult Mouse Brain

“…The mycotoxin OTA, which is found in many foodstuffs [4,5], produces a toxic effect in various organisms. It has been described as carcinogenic, nephro-, immuno-, and genotoxic, is related to increased oxidative stress [6], and is considered neurotoxic [25][26][27]29,30]. For humans, however, hazard identification has been more difficult.…”

“…dose of 3.5 mg OTA/kg body weight (equivalent to approximately 10% of the LD50) in a volume of 2.8 µL/g body weight. This dose was selected because it is in the range of doses used by other studies; in this way, the obtained results could be compared easily [30,43]. The animals were divided into four experimental groups with n = 4-5 animals each: OTA1, OTA2, OTA3, and OTA6, which each received one, two, three, or six doses, respectively.…”

Scientific opinion on the exposure of the adult population of the Republic of Croatia to ochratoxin A (OTA) from different types of food

“…U eksperimentalnih životinja OTA pokazuje aditivni i sinergistički nefrotoksični učinak s drugim mikotoksinima, kao što su citrinin (CIT) i fumonizin B1 (FB1), koji se istovremeno pojavljuju u hrani (Šegvić Klarić i sur., 2013., Heussner i Bingle, 2015Rašić i sur., 2019;Karaica i sur., 2020.). Izloženost ljudi OTA može uzrokovati kroničnu intersticijsku nefropatiju (CIN) i kortikalnu intersticijsku nefropatiju (Schwerdt et al, 2021. ) dok je rak bubrega i uroteladokazan kod štakora (Herman i Mantle, 2021.).…”

Chemical Contamination in Bread from Food Processing and Its Environmental Origin

“…The provisional maximum tolerable daily intake (PMTDI) was set to 2 μg/kg BW for FUMs (FB1, FB2, FB3—alone or in combination) [ 141 ]. OTA, as a possible human carcinogen [ 130 ], induces genotoxic effects in HepG2 cells [ 142 ], impacts human renal cells [ 143 ], and causes acute kidney injuries [ 144 ]. A BMDL10 of 4.73 µg/kg BW/day for non-neoplastic effects and 14.5 µg/kg BW/day for neoplastic effects was set for OTA [ 145 ].…”