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      Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters

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          Abstract

          Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC 50 value of 1.34 μM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase-mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in ischemic acute kidney injury.

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          Most cited references 31

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          Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity.

          In uremic patients, various uremic toxins are accumulated and exert various biologic effects on uremia. Indoxyl sulfate (IS) is one of uremic toxins that is derived from dietary protein, and serum levels of IS are markedly increased in both uremic rats and patients. It has been previously reported that the accumulation of IS promotes the progression of chronic renal failure (CRF). This study demonstrates the role of rat organic anion transporters (rOATs) in the transport of IS and the induction of its nephrotoxicity. The administration of IS to 5/6-nephrectomized rats caused a faster progression of CRF, and immunohistochemistry revealed that IS was detected in the proximal and distal tubules where rOAT1 (proximal tubules) and/or rOAT3 (proximal and distal tubules) were also shown to be localized. In in vitro study, the proximal tubular cells derived from mouse that stably express rOAT1 (S2 rOAT1) and rOAT3 (S2 rOAT3) were established. IS inhibited organic anion uptake by S2 rOAT1 and S2 rOAT3, and the Ki values were 34.2 and 74.4 microM, respectively. Compared with mock, S2 rOAT1 and S2 rOAT3 exhibited higher levels of IS uptake, which was inhibited by probenecid and cilastatin, organic anion transport inhibitors. The addition of IS induced a decrease in the viability of S2 rOAT1 and S2 rOAT3 as compared with the mock, which was rescued by probenecid. These results suggest that rOAT1 and rOAT3 play an important role in the transcellular transport of IS and the induction of its nephrotoxicity.
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            Clinical review: RIFLE and AKIN – time for reappraisal

            In recent years, the use of the consensus definitions of acute kidney injury (RIFLE and AKIN) in the literature has increased substantially. This indicates a highly encouraging acceptance by the medical community of a unifying definition for acute kidney injury. This is a very important and positive step in the right direction. There remains some variation in how the criteria are interpreted and used in the literature, including use/nonuse of urine output criteria, use of change in estimated glomerular filtration rate rather than change in creatinine, and choice of baseline creatinine. The present review is intended to aid the reader in critically appraising studies using these consensus definitions. Since no single definition will be perfect, a logical next step would be to reconcile existing definitions, moving the medical community towards using a single consensus definition as has been done with sepsis and acute lung injury/acute respiratory distress syndrome. As new data emerge, integration of novel biomarkers into the consensus definition will be a welcome refinement.
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              Indoxyl sulfate is a nephro-vascular toxin.

              Indoxyl sulfate is markedly accumulated in the serum of patients with chronic kidney disease (CKD). The oral sorbent AST-120 reduces the serum levels of indoxyl sulfate in CKD patients by adsorbing indole, a precursor of indoxyl sulfate, in the intestine, and thereby stimulating its excretion in feces. AST-120 is used for the treatment of patients with CKD to slow down the progression of CKD. Indoxyl sulfate is taken up by the cells through organic anion transporters (OAT1 and/or OAT3), and induces cellular production of free radicals such as superoxide by activating nicotinamide adenine dinucleotide phosphate oxidase, especially Nox4, thereby impairing the cellular antioxidative system. Indoxyl sulfate induces free radicals in renal tubular cells and glomerular mesangial cells, and stimulates the progression of CKD. I proposed the protein metabolite theory, which states that endogenous protein metabolites such as indoxyl sulfate play a significant role in the progression of CKD by increasing expressions of transforming growth factor-beta1, tissue inhibitor of metalloproteinase-1, and proalpha1(I)collagen. Indoxyl sulfate also induces free radicals in vascular smooth muscle cells and vascular endothelial cells. Indoxyl sulfate stimulates proliferation and osteoblastic transdifferentiation of vascular smooth muscle cells, and inhibits viability and nitric oxide production of vascular endothelial cells. Indoxyl sulfate promotes aortic calcification and aortic wall thickening in hypertensive rats with expression of osteoblast-specific proteins. In conclusion, indoxyl sulfate is a nephro-vascular toxin that is involved in the progression of not only CKD, but also of cardiovascular disease in CKD patients. Therefore, AST-120 may ameliorate the progression of cardiovascular disease as well as of CKD by removing indoxyl sulfate. Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                13 August 2014
                : 8
                : 1073-1082
                Affiliations
                [1 ]Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
                [2 ]Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan
                [3 ]Department of Hemo-Dialysis, Kumamoto University Hospital, Kumamoto, Japan
                Author notes
                Correspondence: Hideyuki Saito, Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto 860 8556, Japan, Tel/Fax +81 96 373 5820, Email saitohide@ 123456fc.kuh.kumamoto-u.ac.jp
                Article
                dddt-8-1073
                10.2147/DDDT.S67456
                4137993
                25143712
                © 2014 Saigo et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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