Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice.
We have previously shown that exogenous and endogenous A(1) adenosine receptor (A(1)AR) activation protected against renal ischemia-reperfusion (IR) injury in mice by induction and phosphorylation of heat shock protein 27 (HSP27). With global overexpression of HSP27 in mice, however, there was a paradoxical increase in systemic inflammation with increased renal injury after an ischemic insult due to increased NK1.1 cytotoxicity. In this study, we hypothesized that selective renal expression of HSP27 in mice would improve renal function and reduce injury after IR. Mice were subjected to renal IR injury 2 days after intrarenal injection of saline or a lentiviral construct encoding enhanced green fluorescent protein (EGFP) or human HSP27 coexpressing EGFP (EGFP-huHSP27). Mice with kidney-specific reconstitution of huHSP27 had significantly lower plasma creatinine, renal necrosis, apoptosis, and inflammation as demonstrated by decreased proinflammatory cytokine mRNA induction and neutrophil infiltration. In addition, there was better preservation of the proximal tubule epithelial filamentous (F)-actin cytoskeleton in the huHSP27-reconstituted groups than in the control groups. Furthermore, huHSP27 overexpression led to increased colocalization with F-actin in renal proximal tubules. Taken together, these findings have important clinical implications, as they imply that kidney-specific expression of HSP27 through lentiviral delivery is a viable therapeutic option in attenuating the effects of renal IR.
Kim
Minjae
M
Departments of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032-3784, USA.
Park
Sang Won
SW
Kim
Mihwa
M
Chen
Sean W C
SW
Gerthoffer
William T
WT
D'Agati
Vivette D
VD
Lee
H Thomas
HT
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D007673:Kidney Cortex Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D020556:Neutrophil Infiltration; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D015854:Up-Regulation
D000199:Actins; D015415:Biomarkers; D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; D018836:Inflammation Mediators; D011993:Recombinant Fusion Proteins; D003404:Creatinine