scholarly journals Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity

2018 ◽  
Vol 94 (1) ◽  
pp. 689-699 ◽  
Author(s):  
Ling Zou ◽  
Adrian Stecula ◽  
Anshul Gupta ◽  
Bhagwat Prasad ◽  
Huan-Chieh Chien ◽  
...  
Keyword(s):  
Drug Toxicity ◽  
Molecular Mechanisms ◽  
Species Differences ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Anion Transporter

Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis

2008 ◽  
Vol 295 (1) ◽  
pp. F247-F252 ◽  
Author(s):  
Jiarong Chen ◽  
Tomohiro Terada ◽  
Ken Ogasawara ◽  
Toshiya Katsura ◽  
Ken-ichi Inui
Keyword(s):  
Bile Acids ◽  
Cholic Acid ◽  
Molecular Mechanisms ◽  
Competitive Inhibition ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Specific Substrate ◽  
Renal Secretion ◽  
Sd Rats ◽  
Anion Transporter

During cholestasis, bile acids are mainly excreted into the urine, but adaptive renal responses to cholestasis, especially molecular mechanisms for renal secretion of bile acids, have not been well understood. Organic anion transporters (OAT1 and OAT3) are responsible for membrane transport of anionic compounds at the renal basolateral membranes. In the present study, we investigated the pathophysiological roles of OAT1 and OAT3 in terms of renal handling of bile acids. The Eisai hyperbilirubinemic rats (EHBR), mutant rats without multidrug resistance-associated protein 2, showed higher serum and urinary concentrations of bile acids, compared with Sprague-Dawley (SD) rats (wild type). The protein expression level of rat OAT3 was significantly increased in EHBR compared with SD rats, whereas the expression of rat OAT1 was unchanged. The transport activities of rat and human OAT3, but not OAT1, were markedly inhibited by various bile acids such as chenodeoxycholic acid and cholic acid. Cholic acid, glycocholic acid, and taurocholic acid, which mainly increased during cholestasis, are transported by OAT3. The plasma concentration of β-lactam antibiotic cefotiam, a specific substrate for OAT3, was more increased in EHBR than in SD rats despite upregulation of OAT3 protein. This may be due to the competitive inhibition of cefotiam transport by bile acids via OAT3. In conclusion, the present study clearly demonstrated that OAT3 is responsible for renal secretion of bile acids during cholestasis and that the pharmacokinetic profile of OAT3 substrates may be affected by cholestasis.

scholarly journals Renal secretion of hydrochlorothiazide involves organic anion transporter 1/3, organic cation transporter 2, and multidrug and toxin extrusion protein 2-K

2019 ◽  
Vol 317 (4) ◽  
pp. F805-F814
Author(s):  
Jia Yin ◽  
David J. Wagner ◽  
Bhagwat Prasad ◽  
Nina Isoherranen ◽  
Kenneth E. Thummel ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Organic Cation ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion

Hydrochlorothiazide (HCTZ) is the most widely used thiazide diuretic for the treatment of hypertension either alone or in combination with other antihypertensives. HCTZ is mainly cleared by the kidney via tubular secretion, but the underlying molecular mechanisms are unclear. Using cells stably expressing major renal organic anion and cation transporters [human organic anion transporter 1 (hOAT1), human organic anion transporter 3 (hOAT3), human organic cation transporter 2 (hOCT2), human multidrug and toxin extrusion 1 (hMATE1), and human multidrug and toxin extrusion 2-K (hMATE2-K)], we found that HCTZ interacted with both organic cation and anion transporters. Uptake experiments further showed that HCTZ is transported by hOAT1, hOAT3, hOCT2, and hMATE2-K but not by hMATE1. Detailed kinetic analysis coupled with quantification of membrane transporter proteins by targeted proteomics revealed that HCTZ is an excellent substrate for hOAT1 and hOAT3. The apparent affinities ( Km) for hOAT1 and hOAT3 were 112 ± 8 and 134 ± 13 μM, respectively, and the calculated turnover numbers ( kcat) were 2.48 and 0.79 s−1, respectively. On the other hand, hOCT2 and hMATE2-K showed much lower affinity for HCTZ. The calculated transport efficiency ( kcat/ Km) at the single transporter level followed the rank order of hOAT1> hOAT3 > hOCT2 and hMATE2-K, suggesting a major role of organic anion transporters in tubular secretion of HCTZ. In vitro inhibition experiments further suggested that HCTZ is not a clinically relevant inhibitor for hOAT1 or hOAT3. However, strong in vivo inhibitors of hOAT1/3 may alter renal secretion of HCTZ. Together, our study elucidated the molecular mechanisms underlying renal handling of HCTZ and revealed potential pathways involved in the disposition and drug-drug interactions for this important antihypertensive drug in the kidney.

scholarly journals Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 909
Author(s):  
Takehiro Nakano ◽  
Hiroshi Watanabe ◽  
Tadashi Imafuku ◽  
Kai Tokumaru ◽  
Issei Fujita ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Mesenchymal Transition ◽  
Anion Transporter

Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial–mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.

Hepatocyte nuclear factor-4α regulates the human organic anion transporter 1 gene in the kidney

2007 ◽  
Vol 292 (6) ◽  
pp. F1819-F1826 ◽  
Author(s):  
Ken Ogasawara ◽  
Tomohiro Terada ◽  
Jun-ichi Asaka ◽  
Toshiya Katsura ◽  
Ken-ichi Inui
Keyword(s):  
Promoter Activity ◽  
Molecular Mechanisms ◽  
Organic Anion ◽  
Critical Role ◽  
Direct Repeat ◽  
Organic Anion Transporter ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Mobility Shift ◽  
Anion Transporter

Human organic anion transporter 1 (OAT1, SLC22A6), which is localized to the basolateral membranes of renal tubular epithelial cells, plays a critical role in the excretion of anionic compounds. OAT1 is regulated by various pathophysiological conditions, but little is known about the molecular mechanisms regulating the expression of OAT1. In the present study, we investigated the transcriptional regulation of OAT1 and found that hepatocyte nuclear factor (HNF)-4α markedly transactivated the OAT1 promoter. A deletion analysis of the OAT1 promoter suggested that the regions spanning −1191 to −700 base pairs (bp) and −140 to −79 bp were essential for the transactivation by HNF-4α. These regions contained a direct repeat separated by two nucleotides (DR-2), which is one of the consensus sequences binding to HNF-4α, and an inverted repeat separated by eight nucleotides (IR-8), which was recently identified as a novel element for HNF-4α, respectively. An electrophoretic mobility shift assay showed that HNF-4α bound to DR-2 and IR-8 under the conditions of HNF-4α overexpression. Furthermore, under normal conditions, HNF-4α bound to IR-8, and a mutation in IR-8 markedly reduced the OAT1 promoter activity, indicating that HNF-4α regulates the basal transcription of OAT1 via IR-8. This paper reports the first characterization of the human OAT1 promoter and the first gene in the kidney whose promoter activity is regulated by HNF-4α.

scholarly journals Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

2020 ◽  
Vol 29 (6) ◽  
pp. 923-943 ◽  
Author(s):  
James Boocock ◽  
Megan Leask ◽  
Yukinori Okada ◽  
Hirotaka Matsuo ◽  
Yusuke Kawamura ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Association Studies ◽  
Organic Anion ◽  
Serum Urate ◽  
High Serum ◽  
Organic Anion Transporter ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Anion Transporter ◽  
Genome Wide

Abstract High serum urate is a prerequisite for gout and associated with metabolic disease. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control; however, there has been little progress in understanding the molecular basis of the associated loci. Here, we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify 10 new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new candidate loci. By cis- and trans-eQTL colocalization analysis, we identified 34 and 20 genes, respectively, where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose–phosphate pathway and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Functional fine mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1 and HNF4G) with colocalized eQTL containing putative causal SNPs. This systematic analysis of serum urate GWAS loci identified candidate causal genes at 24 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.

Characterization of hepatobiliary organic anion transporter regulation in the Zucker rat

2004 ◽  
Vol 42 (08) ◽  
Author(s):  
A Geier ◽  
CG Dietrich ◽  
C Gartung ◽  
F Lammert ◽  
HE Wasmuth ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporter ◽  
Zucker Rat ◽  
Anion Transporter
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