6β-hydroxytestosterone, a cytochrome P450 1B1-testosterone-metabolite, mediates angiotensin II-induced renal dysfunction in male mice

Ajeeth Pingili, Shyamala Thirunavukkarasu, Mehmet Kara, David Brand, Akemi Katsurada, Dewan S.A. Majid, L. Gabriel Navar, Frank J. Gonzalez, Kafait Malik

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

6β-Hydroxytestosterone, a cytochrome P450 1B1-derived metabolite of testosterone, contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to angiotensin II actions on water consumption and renal function in male Cyp1b1+/+ and Cyp1b1-/- mice. Castration of Cyp1b1+/+ mice or Cyp1b1-/- gene disruption minimized the angiotensin II-induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-Hydroxytestosterone did not alter angiotensin II-induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality in Cyp1b1+/+ mice, but restored these effects of angiotensin II in Cyp1b1-/- or castrated Cyp1b1+/+ mice. Cyp1b1 gene disruption or castration prevented angiotensin II-induced renal fibrosis, oxidative stress, inflammation, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, and angiotensin-converting enzyme. 6β-Hydroxytestosterone did not alter angiotensin II-induced renal fibrosis, inflammation, oxidative stress, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin-converting enzyme in Cyp1b1+/+ mice. However, in Cyp1b1-/- or castrated Cyp1b1+/+ mice, it restored these effects of angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with angiotensin II-induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice.

Original languageEnglish (US)
Pages (from-to)916-926
Number of pages11
JournalHypertension
Volume67
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Hydroxytestosterones
Angiotensin II
Cytochrome P-450 Enzyme System
Testosterone
Kidney
Drinking
Angiotensinogen
Angiotensin Type 1 Receptor
Castration
Urine
Peptidyl-Dipeptidase A
Hypertension
Proteinuria
Osmolar Concentration
Oxidative Stress
Fibrosis
Sodium
Inflammation
Thirst
Renal Hypertension

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

6β-hydroxytestosterone, a cytochrome P450 1B1-testosterone-metabolite, mediates angiotensin II-induced renal dysfunction in male mice. / Pingili, Ajeeth; Thirunavukkarasu, Shyamala; Kara, Mehmet; Brand, David; Katsurada, Akemi; Majid, Dewan S.A.; Navar, L. Gabriel; Gonzalez, Frank J.; Malik, Kafait.

In: Hypertension, Vol. 67, No. 5, 01.05.2016, p. 916-926.

Research output: Contribution to journalArticle

Pingili, Ajeeth ; Thirunavukkarasu, Shyamala ; Kara, Mehmet ; Brand, David ; Katsurada, Akemi ; Majid, Dewan S.A. ; Navar, L. Gabriel ; Gonzalez, Frank J. ; Malik, Kafait. / 6β-hydroxytestosterone, a cytochrome P450 1B1-testosterone-metabolite, mediates angiotensin II-induced renal dysfunction in male mice. In: Hypertension. 2016 ; Vol. 67, No. 5. pp. 916-926.
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