Renal Toxicodynamics of Ochratoxin A: A Pathophysiological Approach

Abstract

Ochratoxin A (OTA) is a secondary fungal metabolite that has been detected in a variety of animal chows, human food and in up to 80% of human blood samples of several Western countries. Its main target is the kidney. OTA is the causing agent of Danish porcine nephropathy and increases the incidence of renal carcinomas and adenomas in rats. Pathophysiological studies revealed that OTA acts on different sites along the nephron. Acute OTA exposure leads to an impairment of postproximal nephron function, predominantly of the collecting duct, resulting in altered electrolyte and titratable acid excretion. The underlying mechanism is most probably a blockade of anion conductance in the plasma membrane at nanomolar concentrations of OTA with subsequent disturbance of cellular acid-base homeostasis as shown in cultured kidney cells. Disturbance of cellular pH homeostasis is probably also involved in OTA-induced transformation of cultured kidney cells. Chronic OTA exposure leads to an additional reduction in the urine concentrating ability. Renal hemodynamics and the secretory function of the proximal tubule are affected by OTA after prolonged but not by acute exposure. OTA increases resistance in the vas efferens with a subsequent decrease in renal blood flow and glomerular filtration rate. Proximal tubular cells respond to OTA with a dramatic reduction in the secretory capacity for organic anions. The resorptive capacity for small molecules like amino acids is affected only to a minor extent, whereas endocytic uptake of albumin is clearly reduced. Furthermore, OTA has a mitogenic potential on rat proximal tubular cells in primary culture if applied in nanomolar concentrations but inhibits cell growth at micromolar concentrations. According to the above-described effects OTA exerts a complex action on renal function depending on the dose and time of exposure. The high incidence of OTA in human food and blood samples taken together with its diverse effects on renal function should attract further attention to this mycotoxin as a possible candidate for renal malfunction of unknown origin in humans.

Effect of the mycotoxin, ochratoxin A, on hormone-stimulated ion transport in a cultured cell model of the renal principal cell

“…Concomitantly, the kidney is also one of the major organs affected by OTA. In vivo studies in rats have demonstrated a very sensitive effect of OTA on post-proximal nephron function [5] with subsequent studies indicating that acute exposure has a predominant effect on reabsorptive transport functions in the distal nephron [4]. The nature of the effect on electrolyte and nutrient excretions, predominately a toxin-induced increase in NaCl excretion and a decrease in K + excretion, confirm an action on the distal nephron/ collecting duct.…”

“…Because of the ubiquitous presence of these fungi, the toxin is commonly found in grains, coffee, wine, animal feed and animal products [3,4,5]. OTA is remarkably stable and remains effective after processing treatments such as cooking, brewing or roasting.…”

“…OTA is remarkably stable and remains effective after processing treatments such as cooking, brewing or roasting. In addition, binding of the toxin to serum proteins such as albumin ensures a relatively long half life in the blood [4]. In populations such as Europe, Canada, the United States and northern Africa, where animal and human serum levels have been monitored, there is a high incidence of measurable to toxic levels in the population [4,11,12,16,20].…”

“…Chronic or high level exposure has more global renal effects including reduction in renal blood flow and glomerular filtration, proximal and distal tubular function, and the development of carcinogenic properties [4,5]. In areas of very high levels of human exposure, epidemiological studies have linked OTA as the causative agent in Balkan endemic nephropathy, renal adenomas and carcinomas [12,16,21].…”

“…Previous studies have shown that acute exposure to nanomolar concentrations of OTA altered the ability of the cells to regulate pH by inhibiting anion conductance. Dome formation in MDCK (Madin Darby canine kidney) cells was also inhibited indicating an effect on salt and water movement [4,5,8]. When a principal cell subclone of the MDCK line (MDCK-C7) was exposed to 100 nM OTA for 48 h, the resultant cell line showed irreversible changes in both function and genotype.…”