© 2016 American Heart Association, Inc. 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.
Pingili, A. K., Thirunavukkarasu, S., Kara, M., Brand, D. D., Katsurada, A., Majid, D. S. A., … Malik, K. U. (2016). 6β-hydroxytestosterone, a cytochrome P450 1B1-testosterone-metabolite, mediates angiotensin II-induced renal dysfunction in male mice. Hypertension, 67(5), 916–926. https://doi.org/10.1161/HYPERTENSIONAHA.115.06936