6β-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice.

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.

• Authors: Ajeeth K Pingili, Shyamala Thirunavukkarasu, Mehmet Kara, David D Brand, Akemi Katsurada, Dewan S A Majid, L Gabriel Navar, Frank J Gonzalez, Kafait U Malik
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 67 Issue 5 Pg. 916-26 (May 2016) ISSN: 1524-4563 [Electronic] United States
• PMID: 26928804 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• Hydroxytestosterones
• RNA, Messenger
• Reactive Oxygen Species
• Angiotensin II
• 6 beta-hydroxytestosterone
• Cytochrome P-450 CYP1B1

Topics

• Analysis of Variance
• Angiotensin II (pharmacology)
• Animals
• Biopsy, Needle
• Castration
• Cytochrome P-450 CYP1B1 (genetics)
• Disease Models, Animal
• Hydroxytestosterones (pharmacology)
• Hypertension (physiopathology)
• Immunohistochemistry
• Kidney Diseases (drug therapy, metabolism, pathology)
• Kidney Function Tests
• Male
• Mice
• Oxidative Stress (drug effects)
• RNA, Messenger (analysis)
• Random Allocation
• Reactive Oxygen Species (metabolism)
• Reference Values
• Risk Factors