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.2007080939v1 19/3/559    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 Xu, Z.-G. Articles by Natarajan, R. Search for Related Content PubMed PubMed Citation Articles by Xu, Z.-G. Articles by Natarajan, R.

Products of 12/15-Lipoxygenase Upregulate the Angiotensin II Receptor

Zhong-Gao Xu^*,, Hang Yuan^*,, Linda Lanting^*, Shu-Lian Li, Mei Wang^*, Narkunaraja Shanmugam^*, Mitsuo Kato^*, Sharon G. Adler, Marpadga A. Reddy^* and Rama Natarajan^*

^* Gonda Diabetes Research Center and Department of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, California; Division of Nephrology, 2^nd Hospital of Jilin University, Changchun, China; Division of Nephrology, Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, California

Correspondence: Dr. Rama Natarajan, Gonda Diabetes Research Center, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-256-4673, ext 62289; Fax: 626-301-8136; E-mail: RNatarajan{at}coh.org

Received for publication August 24, 2007. Accepted for publication November 6, 2007.

Angiotensin II and its type 1 receptor (AT1R) play important roles in the pathogenesis of renal disease and diabetic nephropathy. The 12/15-lipoxygenase pathway of arachidonate metabolism and its lipid products have also been implicated in diabetic nephropathy. However, it is unclear whether 12/15-lipoxygenase regulates expression of AT1R. In cultured rat mesangial cells, we found that the 12/15-lipoxygenase product 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) increased AT1R mRNA and protein expression, primarily by stabilizing AT1R mRNA. Pretreatment with 12(S)-HETE also amplified the signaling effects of angiotensin II, likely due to the increased AT1R expression. Levels of AT1R protein expression decreased when 12/15-lipoxygenase was knocked down with specific short hairpin RNA (shRNA) compared with control cells. Similarly, levels of the AT1 receptor, but not the AT2 receptor, were significantly lower in mesangial cells and glomeruli derived from 12/15-lipoxygenase knockout mice compared with control mice. Reciprocally, stable overexpression of 12/15-lipoxygenase increased AT1R expression in cultured mesangial cells. In vivo, modified siRNA targeting 12/15-lipoxygenase reduced glomerular AT1R expression in a diabetic mouse model. Interestingly, angiotensin II induced greater levels of 12/15-lipoxygenase, TGF-β1, and fibronectin (FN) in AT1R-overexpressing mesangial cells compared with control cells. Therefore, oxidized lipids generated by the 12/15-lipoxygenase-mediated metabolism of arachidonic acid can enhance AT1R expression in mesangial cells and augment the profibrotic effects of angiotensin II.

This article has been cited by other articles:

				E. M. Abdel-Rahman, P. M. Abadir, and H. M. Siragy Regulation of renal 12(S)-hydroxyeicosatetraenoic acid in diabetes by angiotensin AT1 and AT2 receptors Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1473 - R1478. [Abstract] [Full Text] [PDF]

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