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

Mahesha H. Gangadhariah, James M. Luther, Victor Garcia, Paisit Paueksakon, Ming Zhi Zhang, Simon W. Hayward, Harold D. Love, John R. Falck, Vijaya L. Manthati, John D. Imig, Michal L. Schwartzman, Roy Zent, Jorge H. Capdevila, Ambra Pozzi

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 developedworse 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.

Original languageEnglish (US)
Pages (from-to)597-610
Number of pages14
JournalJournal of the American Society of Nephrology
Volume26
Issue number3
DOIs
StatePublished - Mar 1 2015

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Diabetic Nephropathies
Hypertension
Kidney
Wounds and Injuries
Podocytes
Albuminuria
Streptozocin
Androgens
Glomerular Basement Membrane
Renal Hypertension
Eicosanoids
Castration
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Vasoconstriction
Type 1 Diabetes Mellitus
Cytochrome P-450 Enzyme System
Hypertrophy
Disease Progression
Apoptosis
Injections

ASJC Scopus subject areas

  • Nephrology

Cite this

Gangadhariah, M. H., Luther, J. M., Garcia, V., Paueksakon, P., Zhang, M. Z., Hayward, S. W., ... 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

Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy. / Gangadhariah, Mahesha H.; Luther, James M.; Garcia, Victor; Paueksakon, Paisit; Zhang, Ming Zhi; Hayward, Simon W.; Love, Harold D.; Falck, John R.; Manthati, Vijaya L.; Imig, John D.; Schwartzman, Michal L.; Zent, Roy; Capdevila, Jorge H.; Pozzi, Ambra.

In: Journal of the American Society of Nephrology, Vol. 26, No. 3, 01.03.2015, p. 597-610.

Research output: Contribution to journalArticle

Gangadhariah, MH, Luther, JM, Garcia, V, Paueksakon, P, Zhang, MZ, Hayward, SW, Love, HD, Falck, JR, Manthati, VL, Imig, JD, Schwartzman, ML, Zent, R, Capdevila, JH & 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, vol. 26, no. 3, pp. 597-610. https://doi.org/10.1681/ASN.2013090980
Gangadhariah, Mahesha H. ; Luther, James M. ; Garcia, Victor ; Paueksakon, Paisit ; Zhang, Ming Zhi ; Hayward, Simon W. ; Love, Harold D. ; Falck, John R. ; Manthati, Vijaya L. ; Imig, John D. ; Schwartzman, Michal L. ; Zent, Roy ; Capdevila, Jorge H. ; Pozzi, Ambra. / Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 3. pp. 597-610.
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