Expression and Function of Renal Organic Anion Transporters in Cholestasis

Brandoni, Anabel; Torres, Adriana M.

doi:10.5772/36935

Cited by 3 publications

(6 citation statements)

References 70 publications

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“…The differences observed in protein expression for Oat1 and Oat3 in this pathology suggest the existence of differential regulating mechanisms in posttranslational levels for these transporters, as previously proposed [7,30,33,35]. The present results suggest that the degradation mechanisms for both Oat1 and Oat3 are impaired but in an opposite sense.…”

Section: Discussionsupporting

confidence: 56%

“…In the last few years, many studies have reported regulation modifications of renal transporters of the SLC22A family in the presence of some pathologies and their impact on the pharmacokinetics of drugs which are substrates of these transporters [6,10,31,33]. In this context, our laboratory has reported relevant contributions [7,21,26,30,34].…”

Section: Discussionmentioning

confidence: 83%

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Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Bulacio¹,

Hazelhoff²,

Torres³

2012

Pharmacology

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Background/Aims: Calcium overload in vascular smooth muscle is a highly pathogenic event, which progresses with advancing age. Old patients are polymedicated, and several pharmacotherapeutic agents circulate in the plasma as organic anions. The organic anion transporters 1 and 3 (Oat1 and Oat3) are present in renal basolateral membranes, which transport organic anions of pharmacological and physiological interest. This study was designed to evaluate the renal expression and function of Oat1 and Oat3 in rats with vascular calcification. Methods: Vascular calcification was induced by administration of a single dose of vitamin D₃ (300,000 UI/ kg b.w., i.m.) to male Wistar rats 10 days before the experiments. Oat1 and Oat3 expression was assessed by immunoblotting, immunohistochemistry and reverse-transcriptase polymerase chain reaction. The renal clearance of p-aminohippurate (PAH, a prototypical organic anion, substrate of Oat1 and Oat3) was measured by conventional clearance techniques. Results: Oat1 and Oat3 protein levels showed an increase in plasma membranes of renal proximal tubules of treated animals, where both transporters are functional. This could explain the increase observed in the renal clearance of PAH in treated rats. Conclusions: These results suggest the relevance of considering the existence of vascular calcification, which is common in ageing, when organic anion drugs are prescribed.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 83%

Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Bulacio¹,

Hazelhoff²,

Torres³

2012

Pharmacology

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“…In addition, insulin-like growth factor 1 significantly increases Oat3 transport activity and SUMOylation through PKA signaling pathways. [45] Brandoni et al [4,5,33,34] have reported an increase in Oat3 expression in renal cortex homogenates without modifications in basolateral membranes after 21 h of bile duct ligation. These results indicate an increase in the synthesis, although these performed proteins are not already anchored into membranes or a decrease in the degradation of the Oat3 protein.…”

Section: Organic Anion Transporter 3 Slc22a8mentioning

confidence: 98%

“…Several compounds such as dicarboxylates, nucleotides, prostaglandins, antivirals, loop and thiazide diuretics, β-lactam antibiotics, non-steroidal anti-inflammatory drugs, including the prototypical substrate of the classical pathway, para-aminohippurate (PAH) are transported by Oat1. [23,25,27,31,32] Eraly et al [24] have generated a colony of Oat1 knockout mice, observing that the knockout mice show an important loss of organic anion transport (e.g., PAH) both ex vivo (in isolated renal slices) as well as in vivo (as indicated by loss of renal secretion). The loss of furosemide (FS) renal secretion in knockout animals caused altered diuretic responsiveness to this drug [24] .…”

Section: Organic Anion Transporting Polypeptide 1 Slco1a1mentioning

confidence: 99%

“…Double ligation and division of the common bile duct in rodents and in dogs is the most frequent model for obstructive jaundice. [4] In these experimental models, the decrease in bile flow is generally correlated with the increase in cholestatic serum biomarkers, modifications in liver histology, and altered liver functions associated with sinusoidal and canalicular transport. [2,3,5,6] Prolonged obstructive cholestasis modifies the liver function because of an altered uptake, biotransformation, and secretion of endogenous and exogenous compounds.…”

Section: Introductionmentioning

confidence: 99%

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Renal response of solute carrier transporters and related proteins in obstructive jaundice

Torres

2023

Gastroenterol Funct Med

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Obstructive jaundice mainly takes place after cholelithiasis and neoplasms that affect the pancreas and the common bile duct. The liver and kidney eliminate toxins, pharmacotherapeutic drugs, and endogenous metabolites. It has been reported that the alteration of one route of excretion can be compensated by the other route. Modifications in the expression of several carrier proteins have been observed after the impairment of the hepatic function. The present work updates the modifications reported in the renal expression and in the urinary levels of some proteins belonging to the solute carrier family (such as Oatp1, Oat1, Oat3, Oat5, Asbt, and NKCC2) and some proteins related in some way to these ones (such as AQP2,Cav-1, and Cav-2). An increased renal expression of Oatp1, Oat1, Oat3, Oat5, and a decreased abundance of Abst was observed after 21 h of bile duct ligation, explaining the increase in the renal clearance of different compounds that could not be excreted by the liver because the biliary excretion is impaired. Moreover, the decreased expression of NKCC2 and AQP2 together with the increase in medullary renal blood flow could account for the increase in the urinary flow previously reported in this pathological state. In addition, a decreased expression of Cav-1 and an increased expression of Cav-2 in kidneys were reported in the early phase of acute cholestasis. It is well-known that renal function is altered during cholestasis and that the impairment of this organ increases with the time course of cholestasis. Increase urinary levels of NaDC1, Cav-1, andCav-2 together with a decrease of Oat5, plus the absence of modifications of NKCC2 and AQP2 were detected after 21 h of bile duct ligation in the absence of alterations in traditional parameters of renal function. Thus, the urinary levels of these proteins were proposed as a novel panel of biomarkers of the early phase of acute obstructive jaundice.

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Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

Brandoni

Hazelhoff²,

Bulacio³

et al. 2012

WJG

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Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct. The absorption, distribution and elimination of drugs are impaired during this pathology. Prolonged cholestasis may alter both liver and kidney function. Lactam antibiotics, diuretics, non-steroidal anti-inflammatory drugs, several antiviral drugs as well as endogenous compounds are classified as organic anions. The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds. It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions. The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis, such as multidrug resistance-associated protein 2, organic anion transporting polypeptide 1, organic anion transporter 3, bilitranslocase, bromosulfophthalein/bilirubin binding protein, organic anion transporter 1 and sodium dependent bile salt transporter. The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.

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Expression and Function of Renal Organic Anion Transporters in Cholestasis

Cited by 3 publications

References 70 publications

Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Renal Expression and Function of Oat1 and Oat3 in Rats with Vascular Calcification

Renal response of solute carrier transporters and related proteins in obstructive jaundice

Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

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