TY - JOUR
T1 - Low-dose testosterone protects against renal ischemia-reperfusion injury by increasing renal IL-10-to-TNF-α ratio and attenuating T-cell infiltration
AU - Patil, Chetan N.
AU - Wallace, Kedra
AU - La Marca, Babbette D.
AU - Moulana, Mohadetheh
AU - Lopez-Ruiz, Arnaldo
AU - Soljancic, Andrea
AU - Juncos, Luis A.
AU - Grande, Joseph P.
AU - Reckelhoff, Jane F.
N1 - Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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. Lowdose 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.
AB - 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. Lowdose 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.
KW - Acute kidney injury
KW - Androgens
KW - Effector T cells
KW - Inflammation
KW - Males
KW - Th17
UR - http://www.scopus.com/inward/record.url?scp=84984611239&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984611239&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00454.2015
DO - 10.1152/ajprenal.00454.2015
M3 - Article
C2 - 27252490
AN - SCOPUS:84984611239
VL - 311
SP - F395-F403
JO - American journal of physiology. Renal physiology
JF - American journal of physiology. Renal physiology
SN - 0363-6127
IS - 2
ER -