scholarly journals Sex-Differences in Renal Expression of Selected Transporters and Transcription Factors in Lean and Obese Zucker Spontaneously Hypertensive Fatty Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Andrea Babelova ◽  
Birgitta C. Burckhardt ◽  
Waja Wegner ◽  
Gerhard Burckhardt ◽  
Maja Henjakovic
Keyword(s):  
Transcription Factors ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Kidney Cortex ◽  
Mrna Levels ◽  
Spontaneously Hypertensive ◽  
Anion Transporter ◽  
Tubular Lumen ◽  
Pas Staining ◽  
Obese Male

The aim of this study was to identify sex-dependent expression of renal transporter mRNA in lean and obese Zucker spontaneously hypertensive fatty (ZSF1) rats and to investigate the interaction of the most altered transporter, organic anion transporter 2 (Oat2), with diabetes-relevant metabolites and drugs. Higher incidence of glomerulosclerosis, tubulointerstitial fibrosis, and protein casts in Bowman’s space and tubular lumen was detected by PAS staining in obese male compared to female ZSF1 rats. Real-time PCR on RNA isolated from kidney cortex revealed that Sglt1-2, Oat1-3, and Oct1 were higher expressed in kidneys of lean females. Oct2 and Mrp2 were higher expressed in obese males. Renal mRNA levels of transporters were reduced with diabetic nephropathy in females and the expression of transcription factors Hnf1βand Hnf4αin both sexes. The highest difference between lean and obese ZSF1 rats was found for Oat2. Therefore, we have tested the interaction of human OAT2 with various substances using tritium-labeled cGMP. Human OAT2 showed no interaction with diabetes-related metabolites, diabetic drugs, and ACE-inhibitors. However, OAT2-dependent uptake of cGMP was inhibited by furosemide. The strongly decreased expression of Oat2 and other transporters in female diabetic ZSF1 rats could possibly impair renal drug excretion, for example, of furosemide.

scholarly journals Morin Improves Urate Excretion and Kidney Function through Regulation of Renal Organic Ion Transporters in Hyperuricemic Mice

2010 ◽  
Vol 13 (3) ◽  
pp. 411 ◽  
Author(s):  
Cai-Ping Wang ◽  
Xing Wang ◽  
Xian Zhang ◽  
Yun-Wei Shi ◽  
Lei Liu ◽  
...  
Keyword(s):  
Uric Acid ◽  
Renal Dysfunction ◽  
Glucose Transporter ◽  
Organic Anion ◽  
Fractional Excretion ◽  
Organic Anion Transporter ◽  
Mrna Levels ◽  
Ion Transporters ◽  
Beneficial Effects ◽  
Anion Transporter

Purpose. Morin (3,5,7,2′,4′-pentahydroxyflavone), a plant-derived flavonoid, has beneficial effects in animals with various diseases including hyperuricemia and renal dysfunction. Since the decreased renal excretion of uric acid is the hallmark of hyperuricemia and renal dysfunction, here we studied the effects of oral morin administration on renal organic ion transporters in oxonate-induced hyperuricemic mice. Methods. The hyperuricemia in mice was induced by potassium oxonate. Uric acid and creatinine concentrations in urine and serum, and fractional excretion of uric acid (FEUA) were performed to evaluate urate handling. Changes in the expression levels of renal organic ion transporters were detected by Western blotting and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Results. Morin treatment significantly reduced urinary uric acid/creatinine ratio and FEUA, resulting in the reduction of serum uric acid levels in hyperuricemic mice. And kidney dysfunction was also improved after morin treatment in this model. Protein and mRNA levels of renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) were significantly decreased, and renal organic anion transporter (mOAT1) levels were remarkably increased in morin-treated hyperuricemic mice. Morin treatment also blocked down-regulation of renal organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2) in hyperuricemic mice. Conclusion. These results suggest that morin exhibits uricosuric effect via suppressing urate reabsorption and promoting urate secretion in the kidney of hyperuricemic mice and may help to attenuate deleterious effects of hyperuricemia with renal dysfunction.

Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver

2005 ◽  
Vol 289 (5) ◽  
pp. G831-G841 ◽  
Author(s):  
Andreas Geier ◽  
Christoph G. Dietrich ◽  
Sebastian Voigt ◽  
Meenakshisundaram Ananthanarayanan ◽  
Frank Lammert ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Hormone Receptors ◽  
Organic Anion ◽  
Pregnane X Receptor ◽  
Regulatory Elements ◽  
Farnesoid X Receptor ◽  
Organic Anion Transporter ◽  
Mrna Levels ◽  
Anion Transporter ◽  
Tnf Α

Proinflammatory cytokines such as TNF-α and IL-1β lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-α or IL-1β for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF-α induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1β also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1α sites after 4 h by either cytokine, which remained more sustained by TNF-α in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)-α are significantly decreased by TNF-α but only transiently affected by IL-1β. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF-α and IL-1β. Activity of HNF-1α as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-α.

Induction of the multispecific organic anion transporter (cMoat/mrp2) gene and biliary glutathione secretion by the herbicide 2,4,5-trichlorophenoxyacetic acid in the mouse liver

1999 ◽  
Vol 341 (1) ◽  
pp. 105-111 ◽  
Author(s):  
Ana M. WIELANDT ◽  
Valeska VOLLRATH ◽  
Marlene MANZANO ◽  
Soledad MIRANDA ◽  
Luigi ACCATINO ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Flow ◽  
Mouse Liver ◽  
Organic Anion ◽  
Fold Increase ◽  
Organic Anion Transporter ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Anion Transporter ◽  
Trichlorophenoxyacetic Acid

The canalicular multispecific organic anion transporter, cMoat, is an ATP-binding-cassette protein expressed in the canalicular domain of hepatocytes. In addition to the transport of endo- and xenobiotics, cMoat has also been proposed to transport GSH into bile, the major driving force of bile-acid-independent bile flow. We have shown previously that the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), a peroxisome-proliferator agent, significantly increases bile-acid-independent bile flow in mice. On this basis, the effect of the herbicide on cMoat gene expression was studied. A 3.6-fold increase in cMoat mRNA levels and a 2.5-fold increase in cMoat protein content were observed in the liver of mice fed on a diet supplemented with 0.125% 2,4,5-T. These effects were due to an increased rate of gene transcription (3.9-fold) and were not associated with peroxisome proliferation. Significant increases in bile flow (2.23±0.39 versus 1.13±0.15 μl/min per g of liver; P < 0.05) and biliary GSH output (7.40±3.30 versus 2.65±0.34 nmol/min per g of liver; P < 0.05) were observed in treated animals. The hepatocellular concentration of total glutathione also increased in hepatocytes of treated mice (10.95±0.84 versus 5.12±0.47 mM; P < 0.05), because of the induction (2.4-fold) of the heavy subunit of the γ-glutamylcysteine synthetase (GCS-HS) gene. This is the first model of co-induction of cMoat and GCS-HS genes in vivo in the mouse liver, associated with increased glutathione synthesis and biliary glutathione output. Our observations are consistent with the hypothesis that the cMoat transporter plays a crucial role in the secretion of biliary GSH.

Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat

2004 ◽  
Vol 287 (6) ◽  
pp. R1505-R1516 ◽  
Author(s):  
M. V. St-Pierre ◽  
T. Stallmach ◽  
A. Freimoser Grundschober ◽  
J.-F. Dufour ◽  
M. A. Serrano ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Expression Profiles ◽  
Organic Anion ◽  
Yolk Sac ◽  
Organic Anion Transporter ◽  
Transport Systems ◽  
Mrna Levels ◽  
Maternal Circulation ◽  
Anion Transporters ◽  
Anion Transporter

Physiological cholestasis linked to immature hepatobiliary transport systems for organic anions occurs in rat and human neonates. In utero, the placenta facilitates vectorial transfer of certain fetal-derived solutes to the maternal circulation for elimination. We compared the ontogenesis of organic anion transporters in the placenta and the fetal liver of the rat to assess their relative abundance throughout gestation and to determine whether the placenta compensates for the late maturation of transporters in the developing liver. The mRNA of members of the organic anion transporting polypeptide (Oatp) superfamily, the multidrug resistance protein (Mrp) family, one organic anion transporter (OAT), and the bile acid carriers Na+-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) was quantified by real-time PCR. The most abundant placental transporters were Oatp4a1, whose mRNA increased 10-fold during gestation, and Mrp1. Mrp1 immunolocalized predominantly to epithelial cells of the endoplacental yolk sac, suggesting an excretory role that sequesters fetal-derived solutes in the yolk sac cavity, and faintly to the basal syncytiotrophoblast surface. The mRNA levels of Oatp2b1, Mrp3, and Bsep in the placenta exceeded those in the fetal liver until day 20 of gestation, suggesting that the fetus relies on placental clearance of substrates when expression in the developing liver is low. Mrp3 immunolocalized to the epithelium of the endoplacental yolk sac and less abundantly in the labyrinth zone and endothelium of the maternal arteries. The placental expression of Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b2, Oat, Ntcp, Mrp2, and Mrp6 was low.

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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