Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease
| Autor: | Seiya Okuda, Sho-ichi Yamagishi, Seiya Kato, Kyoko Matsuguma, Tsutomu Imaizumi, Ryo Shibata, Utako Kaneyuki, Yuriko Matsumoto, Hidehiro Matsuoka, Masumi Kimoto, Seiji Ueda, Toshiko Fujimura |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Nephrology Protein-Arginine N-Methyltransferases medicine.medical_specialty Time Factors medicine.medical_treatment Population Renal function Arginine Kidney Nephrectomy Adenoviridae Amidohydrolases Rats Sprague-Dawley Pathogenesis chemistry.chemical_compound Internal medicine medicine Animals education education.field_of_study biology business.industry General Medicine medicine.disease Rats Nitric oxide synthase Kinetics Cholesterol Endocrinology Liver chemistry Hypertension biology.protein Kidney Failure Chronic Asymmetric dimethylarginine business Kidney disease |
| Zdroj: | Journal of the American Society of Nephrology. 17:2176-2183 |
| ISSN: | 1046-6673 |
| Popis: | Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. ADMA is generated by protein methyltransferase (PRMT) and is metabolized mainly by dimethylarginine dimethylaminohydrolase (DDAH). ADMA levels are reported to increase in patients with chronic kidney disease (CKD), thereby playing a role in the pathogenesis of accelerated atherosclerosis in this population. However, the precise mechanism underlying ADMA accumulation in these patients is not fully understood. This study investigated the molecular mechanism for the elevation of ADMA levels in CKD, using a rat remnant kidney model that represents progressive CKD. After male Sprague-Dawley rats underwent baseline measurement of BP and renal function, 5/6 subtotal nephrectomy (5/6Nx) and 4/6 nephrectomy were performed. Plasma and urinary levels of ADMA and symmetric dimethylarginine, an inert isomer of ADMA, were measured by HPLC. Expression levels of PRMT genes and DDAH proteins were analyzed by semiquantitative reverse transcription-PCR and Western blotting, respectively. Plasma ADMA levels were elevated in the Nx groups in proportion to the degree of nephrectomy despite marked increases in renal clearance of ADMA. In contrast, renal clearance of symmetric dimethylarginine was decreased and its plasma levels were increased in the Nx groups. Furthermore, both liver and kidney gene expression of PRMT was increased, whereas DDAH protein expression was decreased in the 5/6Nx group. Plasma ADMA levels were correlated with systolic BP levels. Moreover, adenovirus-mediated DDAH gene transfer into the 5/6Nx rats prevented the elevation of BP levels, which was associated with the reduction of plasma and urinary ADMA levels. The results presented here suggest that decreased DDAH levels as well as increased PRMT gene expression could cause the elevation of plasma ADMA levels, thereby eliciting hypertension in CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of hypertension-related vascular injury in CKD. |
| Databáze: | OpenAIRE |
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