2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2005121379v1 17/8/2176    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsuguma, K. Articles by Okuda, S. Search for Related Content PubMed PubMed Citation Articles by Matsuguma, K. Articles by Okuda, S. Related Collections Related Article

Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease

Kyoko Matsuguma^*, Seiji Ueda^*, Sho-ichi Yamagishi, Yuriko Matsumoto^*, Utako Kaneyuki^*, Ryo Shibata^*, Toshiko Fujimura^*, Hidehiro Matsuoka, Masumi Kimoto, Seiya Kato, Tsutomu Imaizumi and Seiya Okuda^*

^* Division of Nephrology; Division of Cardiovascular Medicine, Department of Medicine; Department of Pathology, Kurume University, School of Medicine, Kurume, Japan; and Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Soja, Japan

Address correspondence to: Dr. Seiji Ueda, Division of Nephrology, Department of Medicine, Kurume University, School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. Phone: +81-942-31-7002; Fax: +81-942-31-7763; E-mail: ueda{at}med.kurume-u.ac.jp

Received for publication December 29, 2005. Accepted for publication May 17, 2006.

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.

Related Article

This Month’s Highlights
J. Am. Soc. Nephrol. 2006 17: 2075-2076. [Full Text] [PDF]

This article has been cited by other articles:

				W. Mu, D. A. Long, X. Ouyang, A. Agarwal, P. E. Cruz, C. A. Roncal, T. Nakagawa, X. Yu, W. W. Hauswirth, and R. J. Johnson Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism Am J Physiol Renal Physiol, January 1, 2009; 296(1): F145 - F152. [Abstract] [Full Text] [PDF]

				R. Shibata, S. Ueda, S.-i. Yamagishi, Y. Kaida, Y. Matsumoto, K. Fukami, A. Hayashida, H. Matsuoka, S. Kato, M. Kimoto, et al. Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy Nephrol. Dial. Transplant., November 17, 2008; (2008) gfn630v1. [Abstract] [Full Text] [PDF]

				F. Palm, M. L. Onozato, Z. Luo, and C. S. Wilcox Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3227 - H3245. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin, M. L. Lipman, and J. F.E. Mann Chronic Kidney Disease: Effects on the Cardiovascular System Circulation, July 3, 2007; 116(1): 85 - 97. [Abstract] [Full Text] [PDF]

				Y. Matsumoto, S. Ueda, S.-i. Yamagishi, K. Matsuguma, R. Shibata, K. Fukami, H. Matsuoka, T. Imaizumi, and S. Okuda Dimethylarginine Dimethylaminohydrolase Prevents Progression of Renal Dysfunction by Inhibiting Loss of Peritubular Capillaries and Tubulointerstitial Fibrosis in a Rat Model of Chronic Kidney Disease J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1525 - 1533. [Abstract] [Full Text] [PDF]

				Y.-L. Tain, G. Freshour, A. Dikalova, K. Griendling, and C. Baylis Vitamin E reduces glomerulosclerosis, restores renal neuronal NOS, and suppresses oxidative stress in the 5/6 nephrectomized rat Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1404 - F1410. [Abstract] [Full Text] [PDF]

				S. Tatematsu, S. Wakino, T. Kanda, K. Homma, K. Yoshioka, K. Hasegawa, N. Sugano, M. Kimoto, T. Saruta, and K. Hayashi Role of Nitric Oxide-Producing and -Degrading Pathways in Coronary Endothelial Dysfunction in Chronic Kidney Disease J. Am. Soc. Nephrol., March 1, 2007; 18(3): 741 - 749. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673