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NDT Advance Access published online on July 2, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn357
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© The Author [2008].
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org


Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathy

Minoru Satoh1,*, Sohachi Fujimoto1,*, Sayaka Arakawa1, Toyotaka Yada2, Tamehachi Namikoshi1, Yoshisuke Haruna1, Hideyuki Horike1, Tamaki Sasaki1 and Naoki Kashihara1

1 Division of Nephrology, Department of Internal Medicine 2 Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Kurashiki, Okayama, Japan

Correspondence and offprint requests to: Minoru Satoh, Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. Tel: +81-86-462-1111; Fax: +81-86-464-1039; E-mail: msatoh{at}med.kawasaki-m.ac.jp



  Abstract

Background Recent studies showed that angiotensin II type 1 receptor blocker (ARB) slows progression of chronic renal disease in patients with type 2 diabetes, regardless of changes in blood pressure. We showed that the imbalance of nitric oxide (NO) and reactive oxygen species (ROS) due to endothelial NO synthase (eNOS) uncoupling contributed to renal dysfunction in the diabetic nephropathy. The aim of this study was to determine the effects of ARB on uncoupled eNOS in rat diabetic nephropathy.

Methods. Diabetes was induced in Sprague-Dawley rats with streptozotocin (65 mg/ kg body weight). After 6 weeks, rats were divided into saline (DM; n = 11) and ARB, losartan groups (DM+Los; n = 11). After 2-week treatment, glomerular ROS production was assessed by 2',7'-dichlorofluorescin diacetate (DCFH-DA)-derived chemiluminescence. Renal NO and ROS production were imaged by confocal laser microscopy after renal perfusion with DCFH-DA and diaminorhodamine-4M acetoxymethyl ester with L-arginine. The dimeric form of eNOS was measured by low-temperature sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Serum tetrahydrobiopterin (BH4) concentrations were determined by high-performance liquid chromatography. Protein and mRNA expression of GTP cyclohydrolase 1 (GTPCH1), key enzyme of BH4 synthesis, were examined.

Results Losartan attenuated glomerular ROS production in DM. Accelerated ROS production and diminished bioavailable NO caused by NOS uncoupling were noted in DM glomeruli. Losartan reversed the decreased GTPCH1 and decreased dimeric form of eNOS and glomerular NO production by increased BH4 bioavailability.

Conclusions. ARB improved the NOS uncoupling in diabetic nephropathy by increasing BH4 bioavailability.

Keywords: angiotensin II type 1 receptor blocker; endothelial dysfunction; eNOS uncoupling; GTP cyclohydrolase 1; tetrahydrobiopterin

* Contributed equally to this study.

Received for publication: 15. 2.08
Accepted in revised form: 2. 6.08


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