title: 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.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: Ajeeth K
authors.initials: AK
authors.lastname: Pingili
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: Shyamala
authors.initials: S
authors.lastname: Thirunavukkarasu
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kara
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: Akemi
authors.initials: A
authors.lastname: Katsurada
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: Dewan S A
authors.initials: DS
authors.lastname: Majid
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: From the Department of Pharmacology (A.K.P., S.T., M.K., K.U.M.) and Department of Medicine and Microbiology, Immunology and Biochemistry (D.D.B.), College of Medicine, University of Tennessee Health Science Center, Memphis; Veterans Affairs Medical Center, Memphis, TN (D.D.B.); Tulane Hypertension and Renal Center of Excellence, Department of Physiology, School of Medicine, Tulane University, New Orleans, LA (A.K., D.S.A.M., L.G.N.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.). kmalik@uthsc.edu.
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001707:Biopsy, Needle; D002369:Castration; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D004195:Disease Models, Animal; D006915:Hydroxytestosterones / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D012307:Risk Factors
chemical_list: D006915:Hydroxytestosterones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C025591:6 beta-hydroxytestosterone; D065633:Cytochrome P-450 CYP1B1
keywords: 6β-hydroxytestosterone; angiotensinogen; cytochrome P450 1B1; fibrosis