Exposure to nephrotoxic Ochratoxin A enhances collagen secretion in human renal proximal tubular cells

Abstract

Ochratoxin A (OTA) is a nephrotoxic mycotoxin. There is evidence that OTA leads to cortical interstitial nephropathies in humans, associated with fibrosis. No data are available on the effect of OTA-induced collagen secretion from renal cortical cells. As kidney cortex mainly consists of proximal tubules, we investigated the effect of OTA on particular collagens (I, III, IV) in a well-established proximal tubular cell line (opossum kidney (OK) cells) and in primary cultured human renal proximal tubular epithelial cells (RPTECs). In fibroblasts, OTA neither exerted toxic effects nor induced collagen secretion, most probably due to the absence of suitable uptake mechanisms. OTA exerted time- and dose-dependent toxicity in both OK cells and human RPTECs. Moreover, OTA induced collagen secretion in a time- and dose-dependent manner in both cell types. In opposite to transforming growth factor beta1 (TGF-beta1), OTA incubation induced increased apical secretion of the basement membrane collagen IV. This might be evidence for a loss of cellular polarity after OTA incubation. We conclude that in proximal tubular cells, OTA is able to induce extracellular matrix deposition. As collagen secretion was also inducible in primary cultured human RPTECs, we hypothesize that OTA-induced extracellular matrix deposition by proximal tubular cells may be of importance in generation of renal diseases in humans which are under suspicion of being induced by OTA.

Proximal Tubular Toxicity of Ochratoxin A Is Amplified by Simultaneous Inhibition of the Extracellular Signal-Regulated Kinases 1/2

“…We could show previously that OTA induces fibrosis in proximal tubular cells (Sauvant et al, 2004(Sauvant et al, , 2005. Thus, we investigated the effect of ERK1/2 inhibition on OTA-induced secretion of collagen I, III, and IV by specific ELISA technique (Table 1).…”

“…Therefore, we recently investigated the effect of OTA on selected parameters of chronic renal cortical disease in proximal tubular cell lines (Sauvant et al, 2004(Sauvant et al, , 2005. In the mentioned studies, we could show that OTA induces loss of cell number, necrosis and apoptosis, fibrosis, inflammation, and epithelial to mesenchymal transition in proximal tubular cells.…”

Effects of repeated ochratoxin exposure on renal cells in vitro

“…Transdifferentiation has furthermore been discussed in relation to BEN (Markovic-Lipkovski, 2002). Indeed, Sauvant and colleagues hypothesized epithelialto-mesenchymal transition because of OTA-induced enhancement of collagen secrection in OK cells and primary human proximal tubular epithelial cells (RPTECs) (Sauvant et al, 2005).…”

“…The latter findings, coupled with the observations that fibroblasts are less susceptible to ochratoxin-mediated toxicity (Grotegut et al, 2001;O'Brien et al, 2001), gave rise to the hypothesis that repeated exposure to ochratoxins alters normal renal epithelial cells, possibly converting them to a more fibroblast-like nature, thus, providing the rudiments for renal fibrosis (van Kooten et al, 2001). Support for this hypothesis was presented by the recent publication of Sauvant et al (2005), who described an increase in collagen synthesis in OK cells and primary human renal proximal tubular epithelial cells (RPTEC) following exposure to OTA. All of these observations are mostly descriptive in nature and need to be further characterized.…”

Ochratoxin A Contamination of Red Chili Peppers from Chile, Bolivia and Peru, Countries with a High Incidence of Gallbladder Cancer

“…OTA has been classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer (IARC, 1993). OTA has been shown to be a nephrotoxic (Sauvant et al, 2005), hepatotoxic (Ayed-Boussema et al, 2012), teratogenic (Wangikar et al, 2005) and immunotoxic (Mechoud et al, 2012) mycotoxin to several species of animals, and it has been reported to cause kidney and liver tumors in mice and rats (Huff, 1991). OTA can be metabolized in the kidney, liver and intestines (Wu et al, 2011).…”