TY - JOUR
T1 - Heme oxygenase-2 protects against ischemic acute kidney injury
T2 - Influence of age and sex
AU - Nath, Karl A.
AU - Garovic, Vesna D.
AU - Grande, Joseph P.
AU - Croatt, Anthony J.
AU - Ackerman, Allan W.
AU - Farrugia, Gianrico
AU - Katusic, Zvonimir S.
AU - Belcher, John D.
AU - Vercellotti, Gregory M.
N1 - Publisher Copyright:
Copyright © 2019 the American Physiological Society
PY - 2019/9
Y1 - 2019/9
N2 - Heme oxygenase (HO) activity is exhibited by inducible (HO-1) and constitutive (HO-2) proteins. HO-1 protects against ischemic and nephrotoxic acute kidney injury (AKI). We have previously demonstrated that HO-2 protects against heme protein-induced AKI. The present study examined whether HO-2 is protective in ischemic AKI. Renal ischemia was imposed on young and aged HO-2+ /+ and HO-2- /- mice. On days 1 and 2 after renal ischemia, there were no significant differences in renal function between young male HO-2+ /+ and HO-2- /- mice, between young female HO-2+ /+ and HO-2- /- mice, or between aged female HO-2+ /+ and HO-2- /- mice. However, in aged male mice, HO-2 deficiency worsened renal function on days 1 and 2 after ischemic AKI, and, on day 2 after ischemia, such deficiency augmented upregulation of injury-related genes and worsened histological injury. Renal HO activity was markedly decreased in unstressed aged male HO-2- /- mice and remained so after ischemia, despite exaggerated HO-1 induction in HO-2- /- mice after ischemia. Such exacerbation of deficiency of HO-2 protein and HO activity may reflect phosphorylated STAT3, as activation of this proinflammatory transcription factor was accentuated early after ischemia in aged male HO-2- /- mice. This exacerbation may not reflect impaired induction of nephroprotectant genes, since the induction of HO-1, sirtuin 1, and β-catenin was accentuated in aged male HO-2- /- mice after ischemia. We conclude that aged male mice are hypersensitive to ischemic AKI and that HO-2 mitigates such sensitivity. We speculate that this protective effect of HO-2 may be mediated, at least in part, by suppression of phosphorylated STAT3-dependent signaling.
AB - Heme oxygenase (HO) activity is exhibited by inducible (HO-1) and constitutive (HO-2) proteins. HO-1 protects against ischemic and nephrotoxic acute kidney injury (AKI). We have previously demonstrated that HO-2 protects against heme protein-induced AKI. The present study examined whether HO-2 is protective in ischemic AKI. Renal ischemia was imposed on young and aged HO-2+ /+ and HO-2- /- mice. On days 1 and 2 after renal ischemia, there were no significant differences in renal function between young male HO-2+ /+ and HO-2- /- mice, between young female HO-2+ /+ and HO-2- /- mice, or between aged female HO-2+ /+ and HO-2- /- mice. However, in aged male mice, HO-2 deficiency worsened renal function on days 1 and 2 after ischemic AKI, and, on day 2 after ischemia, such deficiency augmented upregulation of injury-related genes and worsened histological injury. Renal HO activity was markedly decreased in unstressed aged male HO-2- /- mice and remained so after ischemia, despite exaggerated HO-1 induction in HO-2- /- mice after ischemia. Such exacerbation of deficiency of HO-2 protein and HO activity may reflect phosphorylated STAT3, as activation of this proinflammatory transcription factor was accentuated early after ischemia in aged male HO-2- /- mice. This exacerbation may not reflect impaired induction of nephroprotectant genes, since the induction of HO-1, sirtuin 1, and β-catenin was accentuated in aged male HO-2- /- mice after ischemia. We conclude that aged male mice are hypersensitive to ischemic AKI and that HO-2 mitigates such sensitivity. We speculate that this protective effect of HO-2 may be mediated, at least in part, by suppression of phosphorylated STAT3-dependent signaling.
KW - Acute kidney injury
KW - Age
KW - Biology of sex differences
KW - Heme oxygenase-2
KW - Phospho-STAT3
UR - http://www.scopus.com/inward/record.url?scp=85071897564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071897564&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00085.2019
DO - 10.1152/ajprenal.00085.2019
M3 - Article
C2 - 31215802
AN - SCOPUS:85071897564
SN - 1931-857X
VL - 317
SP - F695-F704
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 3
ER -