title: Loss of clusterin expression worsens renal ischemia-reperfusion injury.
abstract: Prevention of ischemia-reperfusion injury (IRI) is a challenge in clinical care of the patients with kidney transplants or acute kidney injury, and understanding of the intrinsic mechanisms of resistance to injury in the kidney will lead to a novel therapy. Clusterin, a secreted glycoprotein, is an antiapoptotic protein in cancer cells. Our study is to investigate the role of clusterin in renal IRI. Renal IRI in mice was induced by clamping renal vein and artery for 45 or 50 min at 32 degrees C. Apoptosis of renal tubular epithelial cells (TECs) was determined by FACS analysis. Clusterin expression was examined by Western blot or immunohistochemistry. Here, we showed that clusterin protein was induced in TECs following IRI, and more tubules expressed clusterin in the kidneys following ischemia at higher temperatures. In human proximal TEC HKC-8 cultures, clusterin was upregulated by removal of serum and growth factors in medium and was downregulated by TNF-alpha-IFN-gamma mixture. The levels of clusterin were positively correlated with cell survival in these conditions. Knockdown or knockout of clusterin expression enhanced the sensitivity of TECs to apoptosis. In experimental models of renal IRI, deficiency in clusterin expression worsened the injury, as indicated by a significant increase in renal tissue damage with higher levels of serum creatinine and blood urea nitrogen and by a poorer recovery from the injury in clusterin-deficient mice compared with wild-type mice. Our data indicate that the reduction of inducible expression of clusterin results in an increase in TEC apoptosis in the cultures and renders mice susceptibility to IRI, implying a protective role of clusterin in kidney injury.
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Qiunong
authors.initials: Q
authors.lastname: Guan
authors.forename: Chris C H
authors.initials: CC
authors.lastname: Kwan
authors.forename: Huifang
authors.initials: H
authors.lastname: Chen
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Christopher Y C
authors.initials: CY
authors.lastname: Nguan
authors.forename: Caigan
authors.initials: C
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D051152:Clusterin / Q000172:deficiency* / Q000235:genetics; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003404:Creatinine