NYMC Faculty Publications
Hypertension is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid-Mediated Kidney Injury in Diabetic Nephropathy
Author Type(s)
Faculty
DOI
10.1681/ASN.2013090980
Journal Title
Journal of the American Society of Nephrology
First Page
597
Last Page
610
Document Type
Article
Publication Date
3-1-2015
Department
Pharmacology
Keywords
Animals, Collagen, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 4, Diabetic Nephropathies, Glomerular Basement Membrane, Hydralazine, Hydrochlorothiazide, Hydroxyeicosatetraenoic Acids, Hypertension, Male, Mice, Knockout, Orchiectomy, Renin-Angiotensin System, Reserpine, Sodium
Disciplines
Medicine and Health Sciences
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.
Recommended Citation
Gangadhariah, M. H., Luther, J. M., Garcia, V., Paueksakon, P., Zhang, M., Hayward, S. W., Love, H. D., Falck, J. R., Manthati, V. L., Imig, J. D., Schwartzman, M. L., Zent, R., Capdevila, J. H., & Pozzi, A. (2015). Hypertension is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid-Mediated Kidney Injury in Diabetic Nephropathy. Journal of the American Society of Nephrology, 26 (3), 597-610. https://doi.org/10.1681/ASN.2013090980
