Organic anion transporter 1 (OAT1) involved in renal cell transport of aristolochic acid I

Abstract

Aristolochic acids (AAs) are a family of structurally related nitrophenanthrene carboxylic acids that are present in medicinal herbs such as Aristolochia species. The organic anion transporters (OATs) of the solute carrier (SLC22) gene family located in the renal proximal tubules play a key role in the excretion of a variety of exogenous and endogenous compounds. However, it is unclear how AAs permeate into renal epithelial cells. In this regard, we investigated the role of rat OAT1 ([rOAT1] SLC22A6) in the cellular uptake of AAI in vitro and in vivo. A concentration- and time-dependent intracellular accumulation of AAI was observed in rOAT1-transfected human embryonic kidney 293 (HEK293) cells, which was 2- to 6-fold higher than the control cells. There was a significantly increased rate of cellular apoptosis in rOAT1-transfected HEK293 cells than control cells after AAI treatment. Para-aminohippuric acid (PAH) significantly reduced the intracellular accumulation of AAI in rOAT1-transfected HEK293 cells. Administration of AAI for 35 days in rats caused significantly reduced expression of OAT1 in basolateral membrane and declined renal clearance of PAH as well as renal proximal tubule injuries. These findings indicate that AAI is taken up by OAT1, which then exert its intracellular toxic effects on renal proximal tubule cells, which in turn damage functional OAT1 and may further disturb the transport of its substrates.

An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature

“…In addition, various other competition studies conducted in in vitro heterologous expression systems, also evaluated the interaction between AAI and OAT. It appeared that AAI is a high-affinity substrate for human and mouse OAT1 and OAT3 [77,86,91,95,96] but showed weak affinity for the human OAT4 [91]. These results suggest that the influx of AAI in PTEC through OAT1 and OAT3 is more important than their efflux through OAT4.…”

“…Only a few in vivo studies addressing AA transport in PTEC have been described in the literature [95,96,97]. In AA-treated mice, probenecid treatment has been found to decrease the renal distribution and the urinary excretion of AAI [95] but also to reduce tubular necrosis, lymphocytic infiltrate, tubular atrophy as well as fibrosis by blocking AA entry into PTEC as attested by the reduction of DNA-adducts formation [97].…”

Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice

“…However, 90% of urate reabsorption is obtained through renal URAT1. Moreover, renal organic anion transporter 1 (OAT1) localized in the basolateral membrane and ATP-binding cassette transporter G2 (ABCG2) located at the apical membrane have been identified as main secretory urate transporters 6 , 7 .…”

Aristolochic acid I is a substrate of BCRP but not P-glycoprotein or MRP2

“…Researchers also found that AAI was a substrate of organic anion transporter 1 (OAT1) and OAT3, and renal OATs mediated the renal accumulation and renal toxicity of AAI. When inhibiting renal OATs, renal accumulation as well as renal toxicity of AAI would reduce (Xue et al, 2011;Zeng et al, 2012). However, few study cares for the AAI transport by intestinal efflux transporters.…”