Human heat shock protein 27-overexpressing mice are protected against acute kidney injury after hepatic ischemia and reperfusion.
Liver ischemia-reperfusion injury (IRI) causes acute kidney injury (AKI) in mice characterized by renal endothelial cell apoptosis, renal tubular necrosis, inflammation, and filamentous (F)-actin disruption. Since heat shock protein 27 (HSP27) protects against apoptosis, necrosis, and stabilizes F-actin, we questioned whether overexpression of human HSP27 (huHSP27 OE) in mice would attenuate AKI after liver IRI. Twenty-four hours after hepatic IRI, HSP27 wild-type (WT) mice developed acute liver and kidney injury with elevated plasma alanine aminotransferase and creatinine, a reduced glomerular filtration rate, and histological evidence of renal endothelial cell apoptosis and tubular injury (necrosis, vacuolization, and F-actin disruption). The huHSP27 OE mice, however, were significantly protected against both liver and kidney injury after hepatic IRI. The huHSP27 OE mice also showed less induction of several proinflammatory mRNAs (TNF-alpha, MIP-2, and keratinocyte-derived cytokine), neutrophil infiltration, and reduction in apoptosis (terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling assay and DNA laddering) in the kidney compared with the HSP27 WT mice. Moreover, the huHSP27 OE mice showed significantly less disruption of F-actin in renal proximal tubules and better preserved vascular endothelial cell integrity compared with the huHSP27 OE mice. Finally, the kidney plays a major role in the hepatoprotective effects of huHSP27 overexpression as the hepatoprotection was reduced or abolished in mice subjected to unilateral or bilateral nephrectomy, respectively. Our results show that overexpression of huHSP27 protects against hepatic injury and AKI associated with liver IRI in vivo. Harnessing the mechanisms of cytoprotection with renal HSP27 may lead to new therapies for the perioperative AKI and liver injury associated with liver IRI.
Park
Sang Won
SW
Dept. of Anesthesiology, Anesthesiology Research Laboratories, Columbia Univ., P&S Box 46 (PH-5 630 W. 168th St., New York, NY 10032-3784, USA.
Chen
Sean W C
SW
Kim
Mihwa
M
D'Agati
Vivette D
VD
Lee
H Thomas
HT
D000199:Actins / Q000378:metabolism; D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D054426:Chemokine CXCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004802:Eosinophilia / Q000209:etiology / Q000473:pathology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D007964:Leukocytosis / Q000209:etiology / Q000473:pathology; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009392:Nephrectomy; D009393:Nephritis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000199:Actins; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C074302:keratinocyte-derived chemokines