The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice.
Aging is thought to be associated with a higher susceptibility to renal ischemia-reperfusion injury (IRI). To study whether defective induction of hemeoxygenase-1 (HO-1, a protective and anti-inflammatory enzyme) might contribute to this, we found that while 12-month-old mice had similar baseline renal function and HO-1 expression, the induction of HO-1 usually seen in ischemia-reperfusion was reduced. This was also associated with worsened renal function and acute tubular necrosis in the aged compared with young mice. In the older mice, heme arginate (HA) induced HO-1 in the cortex and medulla, significantly improved renal function, and reduced tissue injury. Cellular HO-1 induction in the medulla in response to injury or HA treatment was found to be interstitial rather than epithelial, as evidenced by its colocalization with macrophage markers. In vitro, HA treatment of primary macrophages resulted in marked HO-1 induction without impairment of classical activation pathways. Macrophage depletion, caused by diphtheria toxin treatment of 12-month-old CD11b-DTR transgenic animals, resulted in the loss of interstitial HO-1-positive cells and reversal of the protective phenotype of HA treatment. Thus, failure of HO-1 induction following renal IRI worsens structural and functional injury in older mice and represents a therapeutic target in the elderly. Hence, HO-1-positive renal macrophages mediate HA-induced protection in IRI.
MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. dferenbach@hotmail.com
David A
DA
Ferenbach
Noemie C J
NC
Nkejabega
Jennifer
J
McKay
Abhijeet K
AK
Choudhary
Madeleine A
MA
Vernon
Matthew F
MF
Beesley
Spike
S
Clay
Bryan C
BC
Conway
Lorna P
LP
Marson
David C
DC
Kluth
Jeremy
J
Hughes
D058186:Acute Kidney Injury / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D000375:Aging; D000818:Animals; D001120:Arginine / Q000627:therapeutic use; D002478:Cells, Cultured; D006418:Heme / Q000627:therapeutic use; D051547:Heme Oxygenase-1 / Q000502:physiology*; D007668:Kidney / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control
D008565:Membrane Proteins; D006418:Heme; D001120:Arginine; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C048849:heme arginate