Structure of renal organic anion and cation transporters

Burckhardt, Gerhard; Wolff, Natascha A.

doi:10.1152/ajprenal.2000.278.6.f853

Cited by 255 publications

(245 citation statements)

References 67 publications

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“…As in this concentration range, NDGA is also an inhibitor of COX (36). In contrast, inhibition of COX by indomethacin ( Figure 6C; IC 50 ϭ approximately 1 M according to manufacturer) at low concentrations completely abolished basolateral PAH uptake. As shown in Figure 6C, the inhibition by indomethacin was dose-dependent with an IC 50 value of approximately 1 M. Because our HPLC data show that only COX metabolites are produced after EGF incubation, prostaglandins are the only candidates for mediating the effect of EGF; we therefore investigated the role of COX in more detail.…”

Section: Cox Metabolites Mediate Egf Stimulation Of Organic Anion Uptakementioning

confidence: 92%

“…Inhibition of cytochrome P450 activity by increasing concentrations of 17-octadeynoic acid (17-ODYA; IC 50 ϭ 5 to 7 M; [29]) did not influence the initial basolateral PAH uptake rate as shown in Figure 6A. In contrast, inhibition of lipoxygenase by nordihydroguaiaretic acid ( Figure 6B; NDGA, IC 50 ϭ approximately 50 M [35]) affected PAH uptake only at 100 M but not at lower concentrations. This effect of NDGA at high concentrations cannot be interpreted unequivocally in a way that lipoxygenases are involved, due to the lack of specificity of NDGA at these high concentrations.…”

Section: Cox Metabolites Mediate Egf Stimulation Of Organic Anion Uptakementioning

confidence: 99%

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Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Sauvant¹,

Holzinger²,

Gekle³

2002

Journal of the American Society of Nephrology

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Abstract. The organic anion transport system of the kidney is of major importance for the excretion of a variety of endogenous compounds, drugs, and potentially toxic substances. The basolateral uptake into proximal tubular cells is mediated by a tertiary active transport system. Epidermal growth factor (EGF) leads to an increase in the basolateral uptake rate of the model substrate para-aminohippuric acid (PAH) in opossum kidney (OK) cells. This stimulation is mediated by successive activation of the mitogen-activated protein kinases, mitogenactivated/extracellular signal-regulated kinase kinase (MEK) and extracellular regulated kinase isoforms 1 and 2 (ERK1/2). This study investigates the regulatory network of EGF action on PAH uptake downstream ERK1/2 in more detail. EGF stimulation of the basolateral uptake rate of [ 14 C]PAH was abolished by the phospholipase A 2 inhibitor AACOCF3. [ 14 C]PAH uptake was enhanced by arachidonic acid. Furthermore, EGF led to an increase in arachidonic acid release and to the generation of prostaglandins. AACOCF3 did not influence EGF-induced ERK1/2 activation, indicating that ERK1/2 is upstream of PLA 2 . In addition, EGF stimulated the influx of extracellular Ca 2ϩ . However, Ca 2ϩ -influx was not required for the stimulatory action of EGF on [ 14 C]PAH uptake. Inhibitors of COX and lipoxygenases reduced [ 14 C]PAH uptake dosedependently, whereas inhibition of cytochrome P450 did not. In the presence of indomethacin, EGF had no stimulatory effect on [ 14 C]PAH uptake. The inhibitory effect of indomethacin was not due to competitive action on PAH uptake. Furthermore, prostaglandin E 2 (PGE 2 ) increased basolateral [ 14 C]PAH uptake rate dose-dependently, and this increase was also observed in the presence of indomethacin. Selective inhibition of COX2 by indomethacin amid or indomethacin n-heptyl ester did not inhibit [ 14 C]PAH uptake, whereas selective inhibition of COX1 dose-dependently inhibited [ 14 C]PAH uptake. This and previous data lead to the conclusion that EGF successively activates MEK, ERK1/2, and PLA 2 , leading to an increased release of arachidonic acid. Subsequently, arachidonic acid is metabolized to prostaglandins via COX1, which then mediate EGF-induced stimulation of basolateral organic anion uptake rate.The organic anion transport system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds (1). This system consists of a basolaterally located organic anion exchanger and a less well characterized transport step at the apical membrane (2).The basolateral organic anion exchanger is a tertiary active transport system, dependent on an inward-directed Na ϩ -gradient to drive the uptake of ␣-ketoglutarate, which is then exchanged for organic anions (1-4). The basolateral exchanger for organic anions and dicarboxylates was cloned by three independent groups (5-7) in 1997 and named OAT1 (rat), ROAT1 (rat), or fROAT1 (winter flounder). The homologous protein was cloned from human kidney only recently and wa...

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Section: Cox Metabolites Mediate Egf Stimulation Of Organic Anion Uptakementioning

confidence: 92%

Section: Cox Metabolites Mediate Egf Stimulation Of Organic Anion Uptakementioning

confidence: 99%

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Sauvant¹,

Holzinger²,

Gekle³

2002

Journal of the American Society of Nephrology

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“…Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4). The transport mechanisms of urate are localized in the proximal tubule (PT), whereas no experimental evidence supports urate permeability in the more distal segments of the nephron (5). URAT1, the long-hypothesized apical urate-anion exchanger involved in the reabsorption of urate by PT cells, was recently identified (6).…”

Section: Abstract Familial Juvenile Hyperuricemic Nephropathy (Fjhn mentioning

confidence: 99%

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Dahan¹,

Devuyst²,

Smaers³

et al. 2003

Journal of the American Society of Nephrology

198

168

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Abstract. Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/ MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disorder characterized by hyperuricemia and decreased urinary excretion of urate, followed by the development of chronic interstitial nephritis most often leading to progressive renal failure (1,2). The link between early hyperuricemia and subsequent progression of renal disease remains unclear.Urate is the end product of purine metabolism in humans, who have lost the expression of the uricase gene during evolution (3). Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4). The transport mechanisms of urate are localized in the proximal tubule (PT), whereas no experimental evidence supports urate permeability in the more distal segments of the nephron (5). URAT1, the long-hypothesized apical urate-anion exchanger involved in the reabsorption of urate by PT cells, was recently identified (6). Inactivating mutations of URAT1 located on 11q13 are responsible

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“…ochratoxin A). Thus, OAT function is a principal determinant of the mammalian capacity for mitigating substrate toxicity, whether stemming from environmental, iatrogenic or endogenous sources [3,4,10,11,40].…”

Section: Introductionmentioning

confidence: 99%

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

190

236

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Our understanding of the mechanisms behind inter-and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient-and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.

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Structure of renal organic anion and cation transporters

Cited by 255 publications

References 67 publications

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

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