title: Heme oxygenase-1 ameliorates kidney ischemia-reperfusion injury in mice through extracellular signal-regulated kinase 1/2-enhanced tubular epithelium proliferation.
abstract: Heme oxygenase (HO)-1 confers transient resistance against oxidative damage, including renal ischemia-reperfusion injury (IRI). We investigated the potential protective effect of HO-1 induction in a mouse model of renal IRI induced by bilateral clamping of the kidney arteries. The mice were randomly assigned to five groups to receive an intraperitoneal injection of PBS, hemin (an HO-1 inducer, 100μmol/kg), hemin+ZnPP (an HO-1 inhibitor, 5mg/kg), hemin+PD98059 (a MEK-ERK inhibitor, 10mg/kg) or a sham operation. All of the groups except for the sham-operated group underwent 25min of ischemia and 24 to 72h of reperfusion. Renal function and tubular damage were assessed in the mice that received hemin or the vehicle treatment prior to IRI. The renal injury score and HO-1 protein levels were evaluated via H&E and immunohistochemistry staining. Hemin-preconditioned mice exhibited preserved renal cell function (BUN: 40±2mg/dl, creatinine: 0.53±0.06mg/dl), and the tubular injury score at 72h (1.65±0.12) indicated that tubular damage was prevented. Induction of HO-1 induced the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. However, these effects were abolished with ZnPP treatment. Kidney function (BUN: 176±49mg/dl, creatinine: 1.54±0.39mg/dl) increased, and the tubular injury score (3.73±0.09) indicated that tubular damage also increased with ZnPP treatment. HO-1-induced tubular epithelial proliferation was attenuated by PD98059. Our findings suggest that HO-1 preconditioning promotes ERK1/2 phosphorylation and enhances tubular recovery, which subsequently prevents further renal injury.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Yuh-Ing Junior College of Health Care & Management, Kaohsiung, Taiwan.
authors.forename: Hsin-Hung
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Bo-Ron
authors.initials: BR
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Division of General Internal Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: wyho@cc.kmu.edu.tw.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Ho
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. Electronic address: cjtseng@vghks.gov.tw.
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
keywords: ERK; HO-1; Hemin; Ischemia-reperfusion injury; Tubular epithelial proliferation; Tubular recovery