title: Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy.
abstract: In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.
authors: Divisions of Nephrology and.
authors: Mahesha H
authors: MH
authors: Gangadhariah
authors: Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
authors: James M
authors: JM
authors: Luther
authors: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors: Victor
authors: V
authors: Garcia
authors: Departments of Pathology Immunology and Microbiology and.
authors: Paisit
authors: P
authors: Paueksakon
authors: Divisions of Nephrology and.
authors: Ming-Zhi
authors: MZ
authors: Zhang
authors: Urologic Surgery; Vanderbilt University, Nashville, Tennessee;
authors: Simon W
authors: SW
authors: Hayward
authors: Urologic Surgery; Vanderbilt University, Nashville, Tennessee;
authors: Harold D
authors: HD
authors: Love
authors: Division of Chemistry, University of Texas Southwestern Medical Center, Dallas, Texas;
authors: John R
authors: JR
authors: Falck
authors: Division of Chemistry, University of Texas Southwestern Medical Center, Dallas, Texas;
authors: Vijaya L
authors: VL
authors: Manthati
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors: John D
authors: JD
authors: Imig
authors: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors: Michal L
authors: ML
authors: Schwartzman
authors: Divisions of Nephrology and Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee.
authors: Roy
authors: R
authors: Zent
authors: Divisions of Nephrology and.
authors: Jorge H
authors: JH
authors: Capdevila
authors: Divisions of Nephrology and Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee ambra.pozzi@vanderbilt.edu.
authors: Ambra
authors: A
authors: Pozzi
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology; D050533:Glomerular Basement Membrane / Q000473:pathology; D006830:Hydralazine; D006852:Hydrochlorothiazide; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006973:Hypertension / Q000150:complications*; D008297:Male; D018345:Mice, Knockout; D009919:Orchiectomy; D012084:Renin-Angiotensin System; D012110:Reserpine; D012964:Sodium / Q000378:metabolism
chemical_list: C436963:Cyp4a14 protein, mouse; D006893:Hydroxyeicosatetraenoic Acids; D006852:Hydrochlorothiazide; D006830:Hydralazine; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D012110:Reserpine; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D000072470:Cytochrome P450 Family 4
keywords: diabetic nephropathy; hypertension; lipids