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

Inducible heat shock proteins (HSP), 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-1functional knock-out 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 creatinines at 24 hours reflow in HSF-KO mice were significantly lower than 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 hour 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.