title: Induction of heat shock protein 70 inhibits ischemic renal injury.
abstract: Heat shock protein 70 (Hsp70) is a potent antiapoptotic agent. Here, we tested whether it directly regulates renal cell survival and organ function in a model of transient renal ischemia using Hsp70 knockout, heterozygous, and wild-type mice. The kidney cortical Hsp70 content inversely correlated with tubular injury, apoptosis, and organ dysfunction after injury. In knockout mice, ischemia caused changes in the activity of Akt and glycogen synthase kinase 3-β (kinases that regulate the proapoptotic protein Bax), increased active Bax, and activated the proapoptotic protease caspase 3. As these changes were significantly reduced in the wild-type mice, we tested whether Hsp70 influences ischemia-induced apoptosis. An Hsp70 inducer, geranylgeranylacetone, increased Hsp70 expression in heterozygous and wild-type mice, and reduced both ischemic tubular injury and organ dysfunction. When administered after ischemia, this inducer also decreased tubular injury and organ failure in wild-type mice but did not protect the knockout mice. ATP depletion in vitro caused greater mitochondrial Bax accumulation and death in primary proximal tubule cells harvested from knockout compared with wild-type mice and altered serine phosphorylation of a Bax peptide at the Akt-specific target site. In contrast, lentiviral-mediated Hsp70 repletion decreased mitochondrial Bax accumulation and rescued Hsp70 knockout cells from death. Thus, increasing Hsp70 either before or after ischemic injury preserves renal function by attenuating acute kidney injury.
authors.affiliation: Renal Section, Boston Medical Center, Evans Biomedical Research Center, Boston, Massachusetts 02118-2518, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gall
authors.forename: Ramon G B
authors.initials: RG
authors.lastname: Bonegio
authors.forename: Andrea
authors.initials: A
authors.lastname: Havasi
authors.forename: Clayton R
authors.initials: CR
authors.lastname: Hunt
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Sherman
authors.forename: John H
authors.initials: JH
authors.lastname: Schwartz
authors.forename: Steven C
authors.initials: SC
authors.lastname: Borkan
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004224:Diterpenes / Q000008:administration & dosage; D015870:Gene Expression; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D007511:Ischemia / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C031049:geranylgeranylacetone