6β‐Hydroxytestosterone, a Cytochrome P4501B1‐Derived Metabolite of Testosterone Plays an Important Role in Renal Dysfunction Associated with Angiotensin II‐Induced Hypertension in Male Mice

Abstract

Recently, we showed that 6β-hydroxytestosterone (6β-OHT), a cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to the development of angiotensin II (Ang II)-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Ang II in renal homeostasis and end organ damage, we determined the contribution of 6β-OHT to Ang II action on water consumption and renal function in male Cyp1b1+/+ and Cyp1b1-/- mice. Eight week old male Cyp1b1+/+ and Cyp1b1-/- intact or castrated mice were injected with 6β-OHT (15 µg/g, i.p. every 3rd day) or vehicle (DMSO, 50 µl), and infused with Ang II (700 ng/kg/min) or vehicle for 2 weeks. Urine was collected for 24 hours on the final day of experiment. Castration or Cyp1b1-/- gene disruption attenuated Ang II-induced increase in water consumption and urine output, proteinuria and decrease in osmolality in Cyp1b1+/+mice (Table 1). 6β-OHT did not alter Ang II-induced increase in water intake, urine output, proteinuria and decrease in osmolality in Cyp1b1+/+ mice, but restored these effects of Ang II in Cyp1b1-/- or castrated mice (Table 1). Cyp1b1 gene disruption or castration prevented Ang II-induced renal fibrosis, inflammation, oxidative stress and AT1 receptor mRNA expression. 6β-OHT did not alter Ang II-induced renal fibrosis, inflammation or oxidative stress in Cyp1b1+/+ mice, however in Cyp1b1-/- or castrated mice it restored these effects of Ang II. These data suggest that 6β-OHT, contributes to increased thirst, impairment of renal function and end organ damage associated with Ang II-induced hypertension in male mice.