2. Academic Validation
  3. Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy

Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy

  • J Am Soc Nephrol. 2015 Mar;26(3):597-610. doi: 10.1681/ASN.2013090980.
Mahesha H Gangadhariah 1,  James M Luther 2,  Victor Garcia 3,  Paisit Paueksakon 4,  Ming-Zhi Zhang 1,  Simon W Hayward 5,  Harold D Love 5,  John R Falck 6,  Vijaya L Manthati 6,  John D Imig 7,  Michal L Schwartzman 3,  Roy Zent 8,  Jorge H Capdevila 1,  Ambra Pozzi 9
Affiliations

Affiliations

  • 1 Divisions of Nephrology and.
  • 2 Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, Tennessee;
  • 3 Department of Pharmacology, New York Medical College, Valhalla, New York;
  • 4 Departments of Pathology Immunology and Microbiology and.
  • 5 Urologic Surgery; Vanderbilt University, Nashville, Tennessee;
  • 6 Division of Chemistry, University of Texas Southwestern Medical Center, Dallas, Texas;
  • 7 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
  • 8 Divisions of Nephrology and Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee.
  • 9 Divisions of Nephrology and Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee ambra.pozzi@vanderbilt.edu.
PMID: 25071086 DOI: 10.1681/ASN.2013090980
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.

Keywords

diabetic nephropathy; hypertension; lipids.

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