Abstract
The mycotoxin, ochratoxin A (OTA), is thought to be responsible for Balkan endemic nephropathy. OTA accumulates in several tissues, especially in the kidneys and liver. The excretion of OTA into urine is thought to be mainly by tubular secretion, presumably via the organic anion transport system. Recently, several families of multispecific organic anion transporters have been identified: organic anion transporters (OATs), organic anion-transporting polypeptides (OATPs), oligopeptide transporters (PEPTs), and ATP-binding cassette (ABC) transporters, such as MRP2 and BCRP. These renal transporters mediate the transmembrane transport of OTA and play a pivotal role in the development of OTA-induced nephrotoxicity.
Highlights
Ochratoxin A (OTA), a structural analog of phenylalanine that contains a chlorinated dihydroisocoumarin moiety [1], is a mycotoxin produced as a secondary metabolite in different species of Aspergillus ochraceus and Penicillium verrucosum [2]
Proliferation of S3 rat kidney-specific organic anion transporter 1 (rOat1) cells was suppressed when exposed to ochratoxin A (OTA) (2 and 10 μM). This suppression was rescued by the addition of para-aminohippuric acid (PAH) (1 mM) to the media. These results indicated that OTA is transported by rOat1 and that the accumulation of OTA via rOat1 in proximal tubular cells is the primary event in the development of OTA-induced nephrotoxicity
Like in the transport of PAH, OTA uptake by hNPT4 was enhanced in the medium with replacement of K+ by Na+. This suggests voltage-driven transport of OTA by hNPT4. hNPT4-mediated OTA uptake was inhibited by several organic anions, such as probenecid and piroxicam. These results indicate that hNPT4 is an apical efflux pathway for OTA entering via basolateral OAT1 or OAT3 in renal proximal tubules (Figure 3)
Summary
Ochratoxin A (OTA), a structural analog of phenylalanine that contains a chlorinated dihydroisocoumarin moiety [1], is a mycotoxin produced as a secondary metabolite in different species of Aspergillus ochraceus and Penicillium verrucosum [2]. OTA mainly impairs proximal tubular functions and causes glucosuria, enzymuria, and a decrease in the transport of para-aminohippuric acid (PAH), a prototypical renal organic anion [11,12,13]. Glomerular filtration of OTA is considered to be minimal, since more than 99% of OTA is bound to plasma proteins [15,16] From these results, it is thought that the excretion of OTA into the urine is mainly by tubular secretion, presumably via the OAT system, and that this may play an important role in OTA accumulation and in the development of nephrotoxicity. We discuss the current idea implicating the function of the renal organic anion transporters as a determinant of OTA-induced nephrotoxicity. For further information concerning the roles of OTA as a signal modulator in the kidney, please refer to a precise review [17]
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