title: Mice that overexpress human heat shock protein 27 have increased renal injury following ischemia reperfusion.
abstract: We previously showed that activation of the A1 adenosine receptor protected the kidney against ischemia-reperfusion injury by induction and phosphorylation of heat shock protein 27 (HSP27). Here, we used mice that overexpress human HSP27 (huHSP27) to determine if kidneys from these mice were protected against injury. Proximal tubule cells cultured from the transgenic mice had increased resistance to peroxide-induced necrosis compared to cells from wild-type mice. However, after renal ischemic injury, HSP27 transgenic mice had decreased renal function compared to wild-type mice, along with increased renal expression of mRNAs of pro-inflammatory cytokines (TNF-alpha, ICAM-1, MCP-1) and increased plasma and kidney keratinocyte-derived cytokine. Following ischemic injury, neutrophils infiltrated the kidneys earlier in the transgenic mice. Flow cytometric analysis of lymphocyte subsets showed that those isolated from the kidneys of transgenic mice had increased CD3(+), CD4(+), CD8(+), and NK1.1(+) cells 3 h after injury. When splenocytes or NK1.1(+) cells were isolated from transgenic mice and adoptively transferred into wild-type mice there was increased renal injury. Further, depletion of lymphocytes by splenectomy or neutralization of NK1.1(+) cells resulted in improved renal function in the transgenic mice following reperfusion. Our study shows that induction of HSP27 in renal tubular cells protects against necrosis in vitro, but its systemic increase counteracts this protection by exacerbating renal and systemic inflammation in vivo.
authors.affiliation: Department of Anesthesiology, Anesthesiology Research Laboratories, College of Physicians and Surgeons, Columbia University, New York, New York 10032-3784, USA.
authors.forename: Sean W C
authors.initials: SW
authors.lastname: Chen
authors.forename: Minjae
authors.initials: M
authors.lastname: Kim
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Song
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Dominic
authors.initials: D
authors.lastname: Wells
authors.forename: Kevin
authors.initials: K
authors.lastname: Brown
authors.forename: Jacqueline de
authors.initials: Jd
authors.lastname: Belleroche
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000032:analysis; D007674:Kidney Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; D018836:Inflammation Mediators; D012333:RNA, Messenger