Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Groves, Carlotta E.; Suhre, Wendy B.; Cherrington, Nathan J.; Wright, Stephen H.

doi:10.1124/jpet.105.094979

Cited by 51 publications

(49 citation statements)

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“…These findings are in agreement with the previously published data on female-dominant expression of mOat3 mRNA and male-dominant expression of mOat1 mRNA and protein in mouse kidneys (9,15,18,39). Our experiments in castrated male mice clearly showed that the expression level of both transporters is dependent on androgens but in opposite directions; castration markedly upregulated the expression of mOat3 protein, suggesting an inhibitory effect of androgens on its expression, whereas the expression of mOat1 protein was downregulated by castration, suggesting a stimulatory effect of androgens on its expression.…”

Section: Discussionsupporting

confidence: 83%

“…7, C and D). These protein data are thus in agreement with the previously reported female-dominant expression of mOat3 mRNA (9,15,39).…”

Section: Characterization Of Roat3-ab By Fluorescence Immunocytochemisupporting

confidence: 82%

“…Previous data indicated that the expression of renal mOat1 is male dominant at both mRNA (9,15,18,39) and protein (18) levels. To support these data, we investigated the expression of renal mOat1 protein by our immunochemical methods.…”

Section: Characterization Of Roat3-ab By Fluorescence Immunocytochemimentioning

confidence: 99%

“…In the mouse kidney, the sex-dependent expression of mOat1 and mOat3 mRNAs has been reported. By using branched DNA signal amplification and real time RT-PCR analysis, three independent groups reported that the expression of renal mOat1 mRNA is significantly higher in male than in female mice (9,15,39). However, the relative expression of renal mOat3 mRNA was different from that of mOat1 mRNA, e.g., it was higher in females than in males in J129 strain, whereas in C57Bl/6 strain of mice, it was sex independent in one study (9) and female dominant in another study (39).…”

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confidence: 99%

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Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Breljak

Brzica

Sweet

et al. 2013

American Journal of Physiology-Renal Physiology

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Breljak D, Brzica H, Sweet DH, Anzai N, Sabolic I. Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys. Am J Physiol Renal Physiol 304: F1114 -F1126, 2013. First published February 6, 2013 doi:10.1152/ajprenal.00201.2012.-In the mouse kidney, organic anion transporter 3 (mOat3, Slc22a8) was previously localized to the basolateral membrane (BLM) of proximal tubule (PT), thick ascending limb of Henle, macula densa, distal tubule, and cortical collecting duct. However, the specificity of antiOat3 antibodies (Oat3-Ab) used in these studies was not properly verified. Moreover, the sex-dependent expression of mOat3, and of the functionally similar transporter mOat1 (Slc22a6), in the mouse kidney has been studied at mRNA level, whereas their protein expression is poorly documented. Here we investigated 1) specificity of Oat3-Abs by using Oat3 knockout (KO) mice, 2) cell localization of renal mOat3 with a specific mOat3-Ab, 3) sex-dependent expression of renal mOat3 and mOat1 proteins, and 4) hormone(s) responsible for observed sex differences. As previously shown, an Oat3-Ab against the rat protein stained the BLM of various nephron segments in wild-type (WT) mice, but the same staining pattern was noted along the nephron of Oat3 KO mice. However, the mOat3-Ab exclusively stained the BLM of PT in WT mice, where it colocalized with the mOat1 protein, whereas no staining of Oat3 protein was noted in the kidney of Oat3 KO mice. The expression of mOat3 protein was lower in male mice, upregulated by castration, and downregulated by testosterone treatment. The expression of mOat1 protein was stronger in males, downregulated by castration, and upregulated by testosterone treatment. Thus, at the protein level, mOat3 and mOat1 exhibit sex-dependent expression with an opposite pattern; mOat3 is female dominant due to androgen inhibition, while mOat1 is male dominant due to androgen stimulation. gender differences; immunocytochemistry; mouse nephron; organic anion transporters; proximal tubule; sex differences; sexual dimorphism; Oat3 knockout IN THE MAMMALIAN KIDNEY, various endogenous and exogenous organic anions (OA), such as anionic metabolites, therapeutic drugs, and environmental toxins, are eliminated by several OA transporters that operate as exchangers and belong to the large family of solute carriers 22 (OAT/SLC22 in humans; Oat/ Slc22 in animals). In proximal tubule epithelial cells, transport of OA from blood to urine is mediated by two distinct types of OATs/Oats; those localized in the basolateral membrane (BLM) mediate the cellular uptake of OA from blood, whereas those localized in the brush border membrane (BBM) mediate the exit of OA into the tubular lumen. In humans and rodents (such as mice and rats), two major BLM transporters responsible for the first step in the renal elimination of a broad range of OA are OAT1/Oat1 (SLC22A6/Slc22a6) and OAT3/Oat3 (SLC22A8/Slc22a8; Refs.

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Section: Discussionsupporting

confidence: 83%

“…7, C and D). These protein data are thus in agreement with the previously reported female-dominant expression of mOat3 mRNA (9,15,39).…”

Section: Characterization Of Roat3-ab By Fluorescence Immunocytochemisupporting

confidence: 82%

Section: Characterization Of Roat3-ab By Fluorescence Immunocytochemimentioning

confidence: 99%

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confidence: 99%

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Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Breljak

Brzica

Sweet

et al. 2013

American Journal of Physiology-Renal Physiology

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“…In addition to the organic cation system, renal tubule cells also display a comparable system for organic anions (20,21). Active transport of organic anions is an essential renal function, and organic anion transporters in the proximal tubule are responsible for transport of p-aminohippurate and hippuran analogs (22,23).…”

Section: Biodistribution and Dosimetrymentioning

confidence: 99%

A PET Tracer for Renal Organic Cation Transporters, ¹¹C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

et al. 2016

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Organic cation transporters (OCTs) in the kidney proximal tubule (PT) participate in renal excretion of drugs and endogenous compounds. PT function is commonly impaired in kidney diseases, and consequently quantitative measurement of OCT function may provide an important estimate of kidney function. Metformin is a widely used drug and targets OCT type 2 located in the PT. Thus, we hypothesized that 11 Clabeled metformin would be a suitable PET tracer for quantification of renal function. Methods: 11 C-metformin was prepared by 11 Cmethylation of 1-methylbiguanide. In vitro cell uptake of 11 C-metformin was studied in LLC-PK 1 cells in the presence of increasing doses of unlabeled metformin. In vivo small-animal PET studies in SpragueDawley rats were performed at baseline and after treatment with OCT inhibitors to evaluate renal uptake of 11 C-metformin. Kidney and liver pharmacokinetics of 11 C-metformin was investigated in vivo by dynamic 11 C-metformin PET/CT in 6 anesthetized pigs, and renal clearance of 11 C-metformin was compared with renal clearance of 51 Cr-ethylenediaminetetraacetic acid (EDTA). Formation of 11 C metabolites was investigated by analysis of blood and urine samples. Results: The radiochemical yield of 11 C-metformin was 15% ± 3% (n 5 40, decay-corrected), and up to 1.5 GBq of tracer were produced with a radiochemical purity greater than 95% in less than 30 min. Dose-dependent uptake of 11 C-metformin in LLC-PK 1 cells was rapid. Rat small-animal PET images showed 11 C-metformin uptake in the kidney and liver, the kinetics of which were changed after challenging animals with OCT inhibitors. In pigs, 80% of the injected metformin dose was rapidly present in the kidney, and a high dose of metformin caused a delayed renal uptake and clearance compared with baseline consistent with transporter-mediated competition. Renal clearance of 11 C-metformin was approximately 3 times the renal clearance of 51 Cr-EDTA. Conclusion: We successfully synthesized an 11 Cmetformin tracer, and PET studies in rats and pigs showed a rapid kidney uptake from the blood and excretion into the bladder similar to other radiopharmaceuticals developed for γ-camera renography.

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Renal Transport of Organic Anions and Cations

Pelis

Wright

2011

Comprehensive Physiology

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Organic anions and cations (OAs and OCs, respectively) comprise an extraordinarily diverse array of compounds of physiological, pharmacological, and toxicological importance. The kidney, primarily the renal proximal tubule, plays a critical role in regulating the plasma concentrations of these organic electrolytes and in clearing the body of potentially toxic xenobiotics agents, a process that involves active, transepithelial secretion. This transepithelial transport involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. Basolateral and luminal OA and OC transport reflects the concerted activity of a suite of separate proteins arranged in parallel in each pole of proximal tubule cells. The cloning of multiple members of several distinct transport families, the subsequent characterization of their activity, and their subcellular localization within distinct regions of the kidney, now allows the development of models describing the molecular basis of the renal secretion of OAs and OCs. New information on naturally occurring genetic variation of many of these processes provides insight into the basis of observed variability of drug efficacy and unwanted drug-drug interactions in human populations. The present review examines recent work on these issues.

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Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Cited by 51 publications

References 30 publications

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

A PET Tracer for Renal Organic Cation Transporters, ¹¹C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

Renal Transport of Organic Anions and Cations

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Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Cited by 51 publications

References 30 publications

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

A PET Tracer for Renal Organic Cation Transporters, 11C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

Renal Transport of Organic Anions and Cations

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Product

Resources

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A PET Tracer for Renal Organic Cation Transporters, ¹¹C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies