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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.

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