title: Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia.
abstract: Heme oxygenase-1 may exert cytoprotective effects. In this study we examined the sensitivity of heme oxygenase-1 knockout (HO-1(-/-)) mice to renal ischemia by assessing glomerular filtration rate (GFR) and cytokine expression in the kidney, and inflammatory responses in the systemic circulation and in vital extrarenal organs. Four hours after renal ischemia, the GFR of HO-1(-/-) mice was much lower than that of wild-type mice in the absence of changes in renal blood flow or cardiac output. Eight hours after renal ischemia, there was a marked induction of interleukin-6 (IL-6) mRNA and its downstream signaling effector, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), in the kidney, lung, and heart in HO-1(-/-) mice. Systemic levels of IL-6 were markedly and uniquely increased in HO-1(-/-) mice after ischemia as compared to wild-type mice. The administration of an antibody to IL-6 protected against the renal dysfunction and mortality observed in HO-1(-/-) mice following ischemia. We suggest that the exaggerated production of IL-6, occurring regionally and systemically following localized renal ischemia, in an HO-1-deficient state may underlie the heightened sensitivity observed in this setting.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Tracz
authors.forename: J P
authors.initials: JP
authors.lastname: Juncos
authors.forename: A J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: A W
authors.initials: AW
authors.lastname: Ackerman
authors.forename: J P
authors.initials: JP
authors.lastname: Grande
authors.forename: K L
authors.initials: KL
authors.lastname: Knutson
authors.forename: G C
authors.initials: GC
authors.lastname: Kane
authors.forename: A
authors.initials: A
authors.lastname: Terzic
authors.forename: M D
authors.initials: MD
authors.lastname: Griffin
authors.forename: K A
authors.initials: KA
authors.lastname: Nath
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000502:physiology; D016207:Cytokines / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051547:Heme Oxygenase-1