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Role of 12-Lipoxygenase in the Stimulation of p38 Mitogen-Activated Protein Kinase and Collagen 5(IV) in Experimental Diabetic Nephropathy and in Glucose-Stimulated Podocytes

Shin-Wook Kang^*, Rama Natarajan, Asha Shahed^*, Cynthia C. Nast, Janine LaPage^*, Peter Mundel, Clifford Kashtan^|| and Sharon G. Adler^*

*Division of Nephrology and Hypertension, Department of Internal Medicine, Harbor-UCLA Research and Education Institute, Torrance, California; Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California; Division of Nephrology, Albert Einstein Medical Center, Bronx, New York; and ^||Department of Pediatric Nephrology, University of Minnesota, Minneapolis, Minnesota

Correspondence to Dr. Sharon Adler, Harbor-UCLA Medical Center, Division of Nephrology and Hypertension, 1000 West Carson Street, Torrance, CA 90509. Phone: 310-222-3891; Fax: 310-782-1837; E-mail: sadler{at}rei.edu

ABSTRACT. The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism is implicated in extracellular matrix (ECM) synthesis, but its role in podocytes has not been studied. This study tested whether 12-LO induction by diabetes or by high glucose (HG) in cultured podocytes alters glomerular basement membrane by activating signal transduction pathways culminating in ECM synthesis. Sprague-Dawley rats received an injection of diluent (control [C]) or streptozotocin 65 mg/kg (DM) and were killed at 1 or 4 mo. Glomerular 12-LO mRNA and protein levels were higher in DM than in C glomeruli at 1 and 4 mo, and 12-LO localized predominantly in podocytes. Glomerular p38 mRNA and protein were higher in DM at months 1 and 4, but phospho-p38 mitogen-activated protein (MAPK) was increased only at month 1. Glomerular collagen 5(IV)/glutaraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio was increased in DM at month 1 but not at month 4, whereas collagen 5(IV) protein was higher at both 1 and 4 mo. Mouse podocytes were cultured in media with 25 mM glucose (HG) with or without the 12-LO inhibitor cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC) or with 5.5 mM glucose + 19.5 mM mannitol (low glucose [LG+M]) for 10 d at 37°C. 12-LO mRNA and protein levels were higher in HG than in LG+M as was the p38 MAPK/GAPDH mRNA ratio. Phospho-p38 MAPK protein but not total p38 MAPK was higher in HG compared with LG+M. Collagen 5(IV)/GAPDH mRNA ratio and protein were higher in HG than in LG+M. 12-LO inhibition by CDC decreased HG-induced phospho-p38 MAPK and the phospho-p38/total p38 MAPK ratio, collagen 5(IV)/GAPDH mRNA ratio, and collagen 5(IV) protein expression. In summary, diabetes in vivo and exposure of podocytes to HG in vitro stimulated 12-LO, p38 MAPK, and collagen 5(IV) mRNA and (activated) protein. 12-LO inhibition by CDC diminished the expression of podocyte phospho-p38 MAPK and collagen 5(IV) mRNA and protein. These findings implicate 12-LO and the p38 MAPK signaling pathway in the mediation of ECM synthesis by podocytes in diabetes.

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