Roles of organic anion transporters (OATs) in renal proximal tubules and their localization

Abstract

Organic anions (OAs) are secreted in renal proximal tubules in two steps. In the first step, OAs are transported from the blood through basolateral membranes into proximal tubular cells. The prototypical substrate for renal organic anion transport systems, para-aminohippurate (PAH), is transported across basolateral membranes of proximal tubular cells via OAT1 (SLC22A6) and OAT3 (SLC22A8) against an electrochemical gradient in exchange for intracellular dicarboxylates. In the second step, OAs exit into urine through apical membranes of proximal tubules. This step is thought to be performed by multidrug efflux transporters and a voltage-driven organic anion transporter. However, the molecular nature and precise functional properties of these efflux systems are largely unknown. Recently, we characterized an orphan transporter known as human type I sodium-phosphate transporter 4, hNPT4 (SLC17A3), using the Xenopus oocyte expression system. hNPT4 acts as a voltage-driven efflux transporter ("human OATv1") for several OAs such as PAH, estrone sulfate, diuretic drugs, and urate. Here, we describe a model for an OA secretory pathway in renal tubular cells in which OAs exit cells and enter the tubular lumen via hOATv1 (hNPT4). Additionally, hOATv1 functions as a common renal secretory pathway for both urate and drugs, indicating that hOATv1 may be a leak pathway for excess urate that is reabsorbed via apical URAT1 to control the intracellular urate levels. Therefore, we propose a molecular mechanism for the induction of hyperuricemia by diuretics: the diuretics enter proximal tubular cells via basolateral OAT1 and/or OAT3 and may then interfere with the NPT4-mediated apical urate efflux in the renal proximal tubule.

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

“…Regarding AA intoxication, several reports have proposed a role for the organic anion (OA) transporter (OAT) family in AA-mediated nephrotoxicity [77,86,87]. OAT family comprises a group of over 10 transmembrane proteins and are members of the solute carrier 22 (SLC22) subfamily [88,89,90]. OAT have been localized to almost all barrier epithelia of the body, as well as in the endothelium [89].…”

“…These transporters have been found to be expressed in many tissues including kidney, liver, intestine, choroid plexus, olfactory mucosa, brain, retina and placenta [89]. OAT are multiselective and may transport many classes of OA, including endogenous substances, such as urate and prostaglandins, but also exogenous molecules, such as antibiotics, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors as well as sulfate and glucuronide conjugates of drugs [90]. In the kidney, OAT substrates are small (molecular weight < 400 to 500 kDa) and water-soluble molecules [88,89] that display an ability to bind albumin [89,90].…”

“…OAT are multiselective and may transport many classes of OA, including endogenous substances, such as urate and prostaglandins, but also exogenous molecules, such as antibiotics, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors as well as sulfate and glucuronide conjugates of drugs [90]. In the kidney, OAT substrates are small (molecular weight < 400 to 500 kDa) and water-soluble molecules [88,89] that display an ability to bind albumin [89,90]. Because of their albumin-binding capacity, these compounds are not filtered through the glomerulus so that they flow further through the peritubular capillaries.…”

Impact of Lesinurad and allopurinol on experimental Hyperuricemia in mice: biochemical, molecular and Immunohistochemical study

“…Over 400 transporters expressed in various tissues throughout the body, comprising members of the solute carrier ATP binding cassette protein families have been reported [40]. OATs family comprises a group of over 10 trans-membrane proteins [41]. OAT1 to − 5 are expressed mainly in the kidney, other members are expressed in remaining other tissues.…”

Uric acid stones, clinical manifestations and therapeutic considerations

“…URAT1 is encoded by the gene SLC22A12 and is expressed in the apical membrane of proximal tubule cells 18. As an apical urate/anion exchanger, URAT1 is responsible for renal urate reabsorption 18 19.…”