Angiotensin II inhibits activity of human organic anion transporter 3 through activation of protein kinase Cα: Accelerating endocytosis of the transporter

Duan, Peng; Li, Shanshan; You, Guofeng

doi:10.1016/j.ejphar.2009.10.048

Cited by 44 publications

(29 citation statements)

References 35 publications

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“…However, the exact mechanisms involved in this process require further studies. It appears that a marked down-regulation of Oat3 arises from an internalization of transport protein by the activation of PKCα [17], [27], [28]. As the profiles of Oat3 activity was closely associated with an impairment of PIK3 function in diabetes in the present study, it is, therefore, reasonable to hypothesize that the effects of PI3K on Oat3 activity observed here may result from modulation of Oat3 trafficking to renal plasma membrane.…”

Section: Discussionsupporting

confidence: 54%

Impaired Insulin Signaling Affects Renal Organic Anion Transporter 3 (Oat3) Function in Streptozotocin-Induced Diabetic Rats

et al. 2014

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Organic anion transporter 3 (Oat3) is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES) uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term) stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K) and protein kinase C zeta (PKCζ) inhibitors inhibited insulin-stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCζ in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCζ/Akt/PKB signaling pathway.

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Section: Discussionsupporting

confidence: 54%

Impaired Insulin Signaling Affects Renal Organic Anion Transporter 3 (Oat3) Function in Streptozotocin-Induced Diabetic Rats

et al. 2014

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“…CQ pretreatment decreased V max without affecting the K m values of OATP1B1-mediated [ 3 H]E 2 17G transport (Figure 8). A similar trend of decreased V max and unaffected K m was reported for OATP1A2 82 and OAT1,3 and 4, 83–85 dopamine transporter, 86 and sodium-glucose transporter (SGLT1) 87 upon PKC activation. In these previous studies, the decreased V max of substrate transport was associated with decreased surface levels for OATP1A2, 82 OAT1, 3 and 4, 83–85 increased phosphorylation for dopamine transporter, 86 or decreased turnover rate but unaltered surface levels for SGLT1.…”

Section: Discussionsupporting

confidence: 77%

Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug-Drug Interactions

et al. 2016

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Organic anion transporting polypeptide (OATP) 1B1 mediates the hepatic uptake of many drugs including lipid-lowering statins. Decreased OATP1B1 transport activity is often associated with increased systemic exposure of statins and statin-induced myopathy. Antimalarial drug chloroquine (CQ) is also used for long-term treatment of rheumatoid arthritis and systemic lupus erythematosus. CQ is lysosomotropic and inhibits protein degradation in lysosomes. The current studies were designed to determine the effects of CQ on OATP1B1 protein degradation, OATP1B1-mediated transport in OATP1B1-overexpressing cell line, and statin uptake in human sandwich-cultured hepatocytes (SCH). Treatment with lysosome inhibitor CQ increased OATP1B1 total protein levels in HEK293-OATP1B1 cells and in human SCH as determined by OATP1B1 immunoblot. In HEK293-FLAG-tagged OATP1B1 stable cell line, co-immunofluorescence staining indicated that intracellular FLAG-OATP1B1 is colocalized with lysosomal associated membrane glycoprotein (LAMP)-2, a marker protein of late endosome/lysosome. Enlarged LAMP-2-positive vacuoles with FLAG-OATP1B1 protein retained inside were readily detected in CQ-treated cells, consistent with blocking lysosomal degradation of OATP1B1 by CQ. In HEK293-OATP1B1 cells, without pre-incubation, CQ concentrations up to 100 μM did not affect OATP1B1-mediated [3H]E217G accumulation. However, pre-incubation with CQ at clinically relevant concentration(s) significantly decreased [3H]E217G and [3H]pitavastatin accumulation in HEK293-OATP1B1 cells and [3H]pitavastatin accumulation in human SCH. CQ pretreatment (25 μM, 2 h) resulted in ∼1.9-fold decrease in Vmax without affecting Km of OATP1B1-mediated [3H]E217G transport in HEK293-OATP1B1 cells. Pretreatment with monensin and bafilomycin A1, which also have lysosome inhibition activity, significantly decreased OATP1B1-mediated transport in HEK293-OATP1B1 cells. Pharmacoepidemiologic studies using data from the U.S. Food and Drug Administration Adverse Event Reporting System indicated that CQ plus pitavastatin, rosuvastatin, and pravastatin, which are minimally metabolized by the cytochrome P450 enzymes, led to higher myopathy risk than these statins alone. In summary, the present studies report novel findings that lysosome is involved in degradation of OATP1B1 protein and that pre-incubation with lysosomotropic drug CQ downregulates OATP1B1 transport activity. Our in vitro data in combination with pharmacoepidemiologic studies support that CQ has potential to cause OATP-mediated drug–drug interactions.

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“…The inhibitory effect of BK on rabbit organic anion transport activity in their study may involve the activation of PKC␣, whereas the stimulatory effect of BK on human OAT3 activity in our current study involves the activation of PKC␦, PKC, and PKCε. Indeed, we have recently shown (Li et al, 2009;Duan et al, 2010) that activation of PKC␣ by angiotensin II exhibits an inhibitory effect on the activities of both hOAT1 and hOAT3, whereas Barros et al (2009) showed that activation of PKC by insulin exhibits an stimulatory effect on the activities of both rat OAT1 and rat OAT3. Active transport of endogenous metabolites and xenobiotics from blood to urine across the cells of the renal proximal tubule is an important protective mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated previously (Zhang et al, 2008;Duan et al, 2010) that both hOAT1 and hOAT3 undergo constitutive internalization and recycling between cell surface and intracellular compartments and that regulation of these transporters can be achieved by altering its already existent trafficking kinetics. We therefore speculate that BK may stimulate hOAT3 activity by either attenuating its internalization, or accelerating its recycling or a combination of both.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Human Organic Anion Transporter 3 by Peptide Hormone Bradykinin

Duan²,

You³

2010

J Pharmacol Exp Ther

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Human organic anion transporter (hOAT) 3 belongs to a family of organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. In the current study, we examined the regulation of hOAT3 by peptide hormone bradykinin (BK) in COS-7 cells. BK (Յ500 nM) induced a concentration-and time-dependent stimulation of hOAT3 activity, kinetically revealed as an increased V max . Such an increase in V max resulted from an increased cell surface expression without a change in total cell expression of the transporter. BK-induced stimulation of hOAT3 activity could be prevented by treating hOAT3-expressing cells with staurosporine, a general inhibitor for protein kinase C (PKC). To obtain further information on which PKC isoform mediates BK regulation of hOAT3 activity, cellular distribution of various PKC isoforms was examined in cells treated with BK. We showed that BK treatment resulted in a significant translocation of PKC␦, PKC, and PKC from cytosol to membrane. We further showed that BK treatment enhanced association of hOAT3 with PKC␦, PKC, and PKC and that isoform-specific inhibitor for PKC␦, PKC, and PKC reversed BK effect on hOAT3 activity. We therefore concluded that BK stimulated hOAT3 activity through activation of PKC␦, PKC, and PKC, which then led to the redistribution of hOAT3 from the intracellular compartments to the cell surface and to the up-regulation of hOAT3 activity.

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Angiotensin II inhibits activity of human organic anion transporter 3 through activation of protein kinase Cα: Accelerating endocytosis of the transporter

Cited by 44 publications

References 35 publications

Impaired Insulin Signaling Affects Renal Organic Anion Transporter 3 (Oat3) Function in Streptozotocin-Induced Diabetic Rats

Impaired Insulin Signaling Affects Renal Organic Anion Transporter 3 (Oat3) Function in Streptozotocin-Induced Diabetic Rats

Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug-Drug Interactions

Regulation of Human Organic Anion Transporter 3 by Peptide Hormone Bradykinin

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