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 mice 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 angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin converting enzyme in Cyp1b1+/+ mice; however, in Cyp1b1−/− or castrated mice 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 males.

2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

“…13,14 In this study treatment with 2-ME inhibited Ang II-induced cardiac and renal fibrosis in male Cyp1b1 +/+ mice (Figure S7). …”

“…14 Treatment with 2-ME in male Cyp1b1 +/+ mice decreased Ang II-induced increase in water intake, urine output, and proteinuria (Figure S3) but did not alter the decrease in osmolality or sodium and potassium excretion in male Cyp1b1 +/+ mice (Figure S4). The values for Ang II alone and its vehicle used for comparison were derived from our previous study.…”

“…The values for Ang II alone and its vehicle used for comparison were derived from our previous study. 14 …”

“…10–12 Recently, we reported that the cytochrome P450 (CYP) 1B1contributes to Ang II-induced hypertension and associated pathophysiological changes in male mice by generating the testosterone metabolite 6β-hydroxytestosterone (6β-OHT). 13–14 In contrast, CYP1B1 was critical for protecting against Ang II-induced hypertension in female mice. 15 Cyp1b1 gene disruption or inhibition of CYP1B1 activity enhanced Ang II-induced increase in systolic blood pressure (SBP) and renal dysfunction in female mice.…”

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…The likely mechanism by which oxidative stress generated via CYP1B1 regulates the activity of these signaling molecules in male mice is depicted in Figure 8. Since testosterone has been implicated in Ang IIeinduced AAA, 56 and because CYP1B1-generated testosterone metabolite 6b-hydroxytestosterone mediates Ang IIeinduced oxidative stress in male mice, 57,58 further studies are being conducted to determine whether this metabolite of testosterone contributes to Ang IIeinduced AAA. In contrast, in female mice, the CYP1B1-generated estradiol metabolite 2-methoxyestradiol is protective against Ang II hypertension, and estradiol ameliorates Ang IIeinduced AAA.…”