Mice with an absent stress response are protected against ischemic renal injury

Kidney Int. 2014 Sep;86(3):515-24. doi: 10.1038/ki.2014.73. Epub 2014 May 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / immunology*
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Creatinine / blood
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Forkhead Transcription Factors
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins / metabolism
  • Interleukin-2 Receptor alpha Subunit
  • Kidney Tubules / immunology*
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / metabolism
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Stress, Physiological / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Antibodies, Monoclonal
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins
  • Hsbp1 protein, mouse
  • Hsf1 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Neoplasm Proteins
  • PC61 monoclonal antibody
  • Transcription Factors
  • Creatinine