Heme oxygenase-2 protects against ischemic acute kidney injury: Influence of age and sex

Karl A. Nath, Vesna D. Garovic, Joseph P. Grande, Anthony J. Croatt, Allan W. Ackerman, Gianrico Farrugia, Zvonimir S. Katusic, John D. Belcher, Gregory M. Vercellotti

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)F695-F704
JournalAmerican Journal of Physiology - Renal Physiology
Issue number3
StatePublished - Sep 2019


  • Acute kidney injury
  • Age
  • Biology of sex differences
  • Heme oxygenase-2
  • Phospho-STAT3

ASJC Scopus subject areas

  • Physiology
  • Urology


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