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.2004070568v1 16/2/352    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 Kim, Y.-S. Articles by Natarajan, R. Search for Related Content PubMed PubMed Citation Articles by Kim, Y.-S. Articles by Natarajan, R.

Novel Interactions between TGF-1 Actions and the 12/15-Lipoxygenase Pathway in Mesangial Cells

Young-Sook Kim^*, Zhong-Gao Xu^*, Marpadga A. Reddy^*, Shu-Lian Li^*, Linda Lanting^*, Kumar Sharma, Sharon G. Adler and Rama Natarajan^*

^* Gonda Diabetes Research Center, Beckman Research Institute of the City of Hope, Duarte, California; Division of Nephrology, Dorrance Hamilton Research Laboratories, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; and Division of Nephrology and Hypertension, Department of Internal Medicine, Harbor-UCLA Research and Education Institute, Torrance, California

Address correspondence to: Dr. Rama Natarajan, Gonda Diabetes Research Center, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-359-8111, ext 62289; Fax: 626-301-8136; rnatarajan{at}coh.org

Diabetic nephropathy (DN) is characterized by mesangial cell (MC) hypertrophy and progressive accumulation of glomerular extracellular matrix (ECM). It was reported recently that 12/15-lipoxygenase (12/15-LO) expression is increased in high-glucose (HG)–stimulated MC and in experimental DN. 12-LO products could also directly induce MC hypertrophy and ECM expression and mediate growth factor effects, thus implicating the 12/15-LO pathway in DN. Because TGF- is a major player in the pathogenesis of DN, whether there is an interplay between the TGF- and 12/15-LO pathways in MC was evaluated. Treatment of rat MC (RMC) with TGF- significantly increased levels of the 12/15-LO product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] and also 12/15-LO mRNA and protein expression. HG-induced TGF- mRNA expression in RMC was inhibited by a specific ribozyme and siRNA targeted to knockdown rat 12/15-LO. It is interesting that direct treatment of RMC with 12(S)-HETE increased TGF- mRNA and protein levels, as well as p-Smad2/3, which are TGF-–specific target transcription factors. 12(S)-HETE also increased transcription from a minimal TGF- promoter. Furthermore, TGF- expression and p-Smad2/3 levels were lower in MC from 12/15-LO knockout mice relative to control mice. Reciprocally, mouse MC stably overexpressing 12/15-LO had greater TGF- mRNA and also nuclear p-Smad2/3 relative to mock-transfected cells. 12/15-LO and TGF- could functionally signal and increase ECM expression via the p38 mitogen-activated protein kinase signaling pathway. These results indicate for the first time that the 12/15-LO and TGF- pathways can cross-talk and activate each other. These novel interactions may amplify the signal transduction cascades and molecular events that lead to DN.

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]

				H. Yuan, L. Lanting, Z.-G. Xu, S.-L. Li, P. Swiderski, S. Putta, M. Jonnalagadda, M. Kato, and R. Natarajan Effects of cholesterol-tagged small interfering RNAs targeting 12/15-lipoxygenase on parameters of diabetic nephropathy in a mouse model of type 1 diabetes Am J Physiol Renal Physiol, August 1, 2008; 295(2): F605 - F617. [Abstract] [Full Text] [PDF]

				Z.-G. Xu, H. Yuan, L. Lanting, S.-L. Li, M. Wang, N. Shanmugam, M. Kato, S. G. Adler, M. A. Reddy, and R. Natarajan Products of 12/15-Lipoxygenase Upregulate the Angiotensin II Receptor J. Am. Soc. Nephrol., March 1, 2008; 19(3): 559 - 569. [Abstract] [Full Text] [PDF]

				M. Guha, Z.-G. Xu, D. Tung, L. Lanting, and R. Natarajan Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes FASEB J, October 1, 2007; 21(12): 3355 - 3368. [Abstract] [Full Text] [PDF]

				I. G. Obrosova, O. Ilnytska, V. V. Lyzogubov, I. A. Pavlov, N. Mashtalir, J. L. Nadler, and V. R. Drel High-Fat Diet Induced Neuropathy of Pre-Diabetes and Obesity: Effects of "Healthy" Diet and Aldose Reductase Inhibition Diabetes, October 1, 2007; 56(10): 2598 - 2608. [Abstract] [Full Text] [PDF]

				M. Kato, J. Zhang, M. Wang, L. Lanting, H. Yuan, J. J. Rossi, and R. Natarajan MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors PNAS, February 27, 2007; 104(9): 3432 - 3437. [Abstract] [Full Text] [PDF]

				M. Kato, H. Yuan, Z.-G. Xu, L. Lanting, S.-L. Li, M. Wang, M. C.-T. Hu, M. A. Reddy, and R. Natarajan Role of the Akt/FoxO3a Pathway in TGF-beta1-Mediated Mesangial Cell Dysfunction: A Novel Mechanism Related to Diabetic Kidney Disease J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3325 - 3335. [Abstract] [Full Text] [PDF]

				J. Cheng, M. M. D. Encarnacion, G. M. Warner, C. E. Gray, K. A. Nath, and J. P. Grande TGF-{beta}1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process Am J Physiol Cell Physiol, October 1, 2005; 289(4): C959 - C970. [Abstract] [Full Text] [PDF]

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