Organic Anion Transporter 3 Contributes to the Regulation of Blood Pressure

Vallon, Volker; Eraly, Satish A.; Wikoff, William R.; Rieg, Timo; Kaler, Gregory; Truong, David M.; Ahn, Sun Young; Mahapatra, Nitish R.; Mahata, Sushil K.; Gangoiti, Jon A.; Wu, Wei; Barshop, Bruce A.; Siuzdak, Gary; Nigám, Sanjay K.

doi:10.1681/asn.2008020180

Cited by 73 publications

(71 citation statements)

References 47 publications

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“…Oocyte transport assays were performed as previously described (41,42). Briefly, capped cRNA was generated via in vitro transcription from linearized plasmid DNA (mOat1, Image clone ID 4163278; mOat3, Image clone ID 4239544) using mMessage mMachine in vitro transcription kit (Ambion, Austin, TX).…”

Section: Methodsmentioning

confidence: 99%

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Vallon

Eraly

Rao

et al. 2012

American Journal of Physiology-Renal Physiology

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102

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Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 ( Oat1−/−) and OAT3 ( Oat3−/−). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1−/− (−0.03 ± 0.10 μg/min; −3 ± 18%) and Oat3−/− (0.01 ± 0.06 μg/min; −6 ± 19%), with greater variability in Oat1−/−. Expression of OAT3 protein in the renal membranes of Oat1−/− mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3−/− mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3−/− were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.

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Section: Methodsmentioning

confidence: 99%

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Vallon

Eraly

Rao

et al. 2012

American Journal of Physiology-Renal Physiology

Self Cite

102

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“…Plasma renin concentration was determined by RIA (GammaCoat; DiaSorin, Stillwater, MN) as the generation of angiotensin I after addition of excess renin substrate from 24-hour nephrectomized rats. 38 As an indirect measure of circulating vasopressin, concentration of vasopressin in urine was measured using a commercial assay (IBL, Hamburg, Germany) and related to creatinine. 39 Urine and plasma osmolalities were measured by vapor pressure (Vapro; Wescor, Salt Lake City, UT).…”

Section: Blood and Urine Analysismentioning

confidence: 99%

“…38,40,41 GFR measurements were performed in conscious mice using the plasma kinetics of FITC-inulin after a single-dose intravenous injection as described previously. 42 …”

Section: Bp Heart Rate and Gfr Measurement In Awake Micementioning

confidence: 99%

SGLT2 Mediates Glucose Reabsorption in the Early Proximal Tubule

Vallon¹,

Platt²,

Cunard³

et al. 2011

Journal of the American Society of Nephrology

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444

430

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Mutations in the gene encoding for the Na ϩ -glucose co-transporter SGLT2 (SLC5A2) associate with familial renal glucosuria, but the role of SGLT2 in the kidney is incompletely understood. Here, we determined the localization of SGLT2 in the mouse kidney and generated and characterized SGLT2-deficient mice. In wild-type (WT) mice, immunohistochemistry localized SGLT2 to the brush border membrane of the early proximal tubule. Sglt2 Ϫ/Ϫ mice had glucosuria, polyuria, and increased food and fluid intake without differences in plasma glucose concentrations, GFR, or urinary excretion of other proximal tubular substrates (including amino acids) compared with WT mice. SGLT2 deficiency did not associate with volume depletion, suggested by similar body weight, BP, and hematocrit; however, plasma renin concentrations were modestly higher and plasma aldosterone levels were lower in Sglt2mice. Whole-kidney clearance studies showed that fractional glucose reabsorption was significantly lower in Sglt2 Ϫ/Ϫ mice compared with WT mice and varied in Sglt2 Ϫ/Ϫ mice between 10 and 60%, inversely with the amount of filtered glucose. Free-flow micropuncture revealed that for early proximal collections, 78 Ϯ 6% of the filtered glucose was reabsorbed in WT mice compared with no reabsorption in Sglt2 Ϫ/Ϫ mice. For late proximal collections, fractional glucose reabsorption was 93 Ϯ 1% in WT and 21 Ϯ 6% in Sglt2 Ϫ/Ϫ mice, respectively. These results demonstrate that SGLT2 mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. This mouse model mimics and explains the glucosuric phenotype of individuals carrying SLC5A2 mutations. 22: 104 -112, 201122: 104 -112, . doi: 10.1681 Glucose is the main source of energy in eukaryotic organisms. The homeostasis of glucose is maintained by intestinal glucose absorption and the coordinated regulation of hepatic and renal glucose production, as well as tissue consumption of glucose. As a consequence of renal glomerular filtration, approximately 180 g/d glucose enter the tubular system of the kidneys in a healthy individual with normoglycemia, which is equivalent to approximately one third of the total energy consumed by the human body. Glucose in urine, however, is absent or at very low concentrations in healthy adults (range 0.03 to 0.30 g/d) as a result of near complete reabsorption along the nephron segments, primarily in the proximal tubule. The genes encoding transporter proteins participating in renal J Am Soc Nephrol

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“…OAT1 and OAT3 knockout mice models manifested a profound loss of organic anion transport, although no obvious morphological or physiological abnormalities were observed [46][47][48][49]. In OAT1 knockout mice, the uptake of its model substrate, Para-Amino Hippurate (PAH) was significantly inhibited in isolated renal slices and urinary secretion, whereas the transport of taurocholate, Estrone-3-Sulfate (ES), PAH, and fluorescein were remarkably reduced in the OAT3-null mice [46,47].…”

Section: Knockout Mice Models Of Oatsmentioning

confidence: 99%

“…In OAT1 knockout mice, the uptake of its model substrate, Para-Amino Hippurate (PAH) was significantly inhibited in isolated renal slices and urinary secretion, whereas the transport of taurocholate, Estrone-3-Sulfate (ES), PAH, and fluorescein were remarkably reduced in the OAT3-null mice [46,47]. Furthermore, OAT3-knockout mice appeared to have a lower renal Blood Pressure (BP) compared to the normal little mates [49], which observation suggested the potential treatment of high blood pressure, through regulating OAT3 function. More recently, Xue et al [48] discovered that OAT1 and OAT3 are responsible for the cellular transport of Aristolochic Acid I (AAI), which agent causes severe kidney injury.…”

Section: Knockout Mice Models Of Oatsmentioning

confidence: 99%