title: Low-dose testosterone protects against renal ischemia-reperfusion injury by increasing renal IL-10-to-TNF-α ratio and attenuating T-cell infiltration.
abstract: Renal ischemia-reperfusion (I/R) in male rats causes reductions in plasma testosterone, and infusion of testosterone 3 h postreperfusion is protective. We tested the hypotheses that acute high doses of testosterone promote renal injury after I/R, and that acute low-dose testosterone is protective by the following: 1) increasing renal IL-10 and reducing TNF-α; 2) its effects on nitric oxide; and 3) reducing intrarenal T-cell infiltration. Rats were subjected to renal I/R, followed by intravenous infusion of vehicle or testosterone (20, 50, or 100 μg/kg) 3 h postreperfusion. Low-dose testosterone (20 μg/kg) reduced plasma creatinine, increased nitrate/nitrite excretion, increased intrarenal IL-10, and reduced intrarenal TNF-α, whereas 50 μg/kg testosterone failed to reduce plasma creatinine, increased IL-10, but failed to reduce TNF-α. A higher dose of testosterone (100 mg/kg) not only failed to reduce plasma creatinine, but significantly increased both IL-10 and TNF-α compared with other groups. Low-dose nitro-l-arginine methyl ester (1 mg·kg(-1)·day(-1)), given 2 days before I/R, prevented low-dose testosterone (20 μg/kg) from protecting against I/R injury, and was associated with lack of increase in intrarenal IL-10. Intrarenal CD4(+) and CD8(+) T cells were significantly increased with I/R, but were attenuated with low-dose testosterone, as were effector T helper 17 cells. The present studies suggest that acute, low-dose testosterone is protective against I/R AKI in males due to its effects on inflammation by reducing renal T-cell infiltration and by shifting the balance to favor anti-inflammatory cytokine production rather than proinflammatory cytokines.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; The Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Chetan N
authors.initials: CN
authors.lastname: Patil
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi; The Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Kedra
authors.initials: K
authors.lastname: Wallace
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, Mississippi; The Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Babbette D
authors.initials: BD
authors.lastname: LaMarca
authors.affiliation: Department of Psychiatry, University of Mississippi Medical Center, Jackson, Mississippi; The Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Mohadetheh
authors.initials: M
authors.lastname: Moulana
authors.affiliation: Department of Medicine (Nephrology), University of Mississippi Medical Center, Jackson, Mississippi;
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Lopez-Ruiz
authors.affiliation: Department of Medicine (Nephrology), University of Mississippi Medical Center, Jackson, Mississippi;
authors.forename: Andrea
authors.initials: A
authors.lastname: Soljancic
authors.affiliation: Department of Medicine (Nephrology), University of Mississippi Medical Center, Jackson, Mississippi;
authors.forename: Luis A
authors.initials: LA
authors.lastname: Juncos
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; The Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi; and jreckelhoff@umc.edu.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Reckelhoff
mesh_terms: D000818:Animals; D003401:Creatine / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016753:Interleukin-10 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000187:drug effects*; D013739:Testosterone / Q000008:administration & dosage / Q000627:therapeutic use*; D058504:Th17 Cells / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013739:Testosterone; D019001:Nitric Oxide Synthase; D003401:Creatine; D019331:NG-Nitroarginine Methyl Ester
keywords: Th17; acute kidney injury; androgens; effector T cells; inflammation; males