title: Mice with an absent stress response are protected against ischemic renal injury.
abstract: Inducible heat shock proteins (HSPs), regulated by heat shock factor-1 (HSF-1), protect against renal cell injury in vitro. To determine whether HSPs ameliorate ischemic renal injury in vivo, HSF-1 functional knockout mice (HSF-KO) were compared with wild-type mice following bilateral ischemic renal injury. Following injury, the kidneys of wild-type mice had the expected induction of HSP70 and HSP25; a response absent in the kidneys of HSF-KO mice. Baseline serum creatinine was equivalent between strains. Serum creatinine at 24 h reflow in HSF-KO mice was significantly lower than that in the wild type. Histology showed similar tubule injury in both strains after ischemic renal injury but increased medullary vascular congestion in wild-type compared with HSF-KO mice. Flow cytometry of mononuclear cells isolated from kidneys showed no difference between strains in the number of CD4(+) and CD8(+) T cells in sham-operated animals. At 1 h of reflow, CD4(+) and CD8(+) cells were doubled in the kidneys of wild-type but not HSF-KO mice. Foxp3(+) T-regulatory cells were significantly more abundant in the kidneys of sham-operated HSF-KO than wild-type mice. Suppression of CD25(+)Foxp3(+) cells in HSF-KO kidneys with the anti-CD25 antibody PC61 reversed the protection against ischemic renal injury. Thus, HSF-KO mice are protected from ischemic renal injury by a mechanism that depends on an increase in the T-regulatory cells in the kidney associated with altered T-cell infiltration early in reflow. Hence, stress response activation may contribute to early injury by facilitating T-cell infiltration into ischemic kidney.
authors.affiliation: Division of Nephrology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.
authors.forename: Rajasree
authors.initials: R
authors.lastname: Sreedharan
authors.affiliation: Division of Nephrology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.
authors.forename: Shaoying
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: Miller
authors.affiliation: Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.
authors.forename: Dipica
authors.initials: D
authors.lastname: Haribhai
authors.affiliation: Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Williams
authors.affiliation: Division of Nephrology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Van Why
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D003404:Creatinine / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit; D007684:Kidney Tubules / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C490017:Hsf1 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; C584092:PC61 monoclonal antibody; D014157:Transcription Factors; D003404:Creatinine