期刊
HYPERTENSION
卷 67, 期 5, 页码 916-926出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.115.06936
关键词
6 beta-hydroxytestosterone; angiotensinogen; cytochrome P450 1B1; fibrosis
资金
- National Institutes of Health
- National Heart, Lung, and Blood Institute [R01HL-19134-40, R01HL-079109-09, R01HL-66432, R01HL26371]
- Department of Veterans Affairs [BX001193-02]
- Tulane Bridge Fund
- National Institute of General Medical Sciences IDeA Program (COBRE) [P30GM103337]
- Department of Pharmacology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
6 beta-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 6 beta-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. 6 beta-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. 6 beta-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 6 beta-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with angiotensin IIinduced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice.
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