Heat shock protein 72 suppresses apoptosis by increasing the stability of X-linked inhibitor of apoptosis protein in renal ischemia/reperfusion injury.
X‑linked inhibitor of apoptosis protein (XIAP) negatively regulates apoptotic pathways at a post‑mitochondrial level. XIAP functions by directly binding and inhibiting activation of specific caspases. Upon apoptotic stimuli, mitochondrial second mitochondria‑derived activator of caspases (Smac)/direct IAP‑binding protein with low PI (Diablo) is released into the cytosol, which results in displacement of XIAP from caspases. Heat shock protein 72 (HSP72), an anti‑apoptotic protein, prevents mitochondrial injury resulting from acute renal ischemia/reperfusion (I/R), its role in Smac/Diablo and XIAP signaling remains to be elucidated. In the present study, the hypothesis that HSP72 prevents XIAP degradation in vivo and in vitro was assessed. To this purpose, a rat model of I/R injury was used to investigate the renoprotective role of HSP72 by treatment with geranylgeranylacetone (GGA), a specific inducer of HSP72. The mechanism of the cytoprotective properties of HSP72 was also investigated in vitro using adenovirus‑mediated overexpression of HSP72 in adenosine triphosphate (ATP)‑depleted human kidney 2 (HK‑2) cells. Pre‑conditioning rats with GGA attenuated renal tubular cell damage, reduced cell apoptosis, preserved XIAP protein content and improved renal function following I/R injury. An in vitro study was performed in which cells were transiently exposed to 5 mM sodium cyanide in a glucose‑free medium in order to induce apoptosis. Compared with the control, overexpression of HSP72 inhibited Smac/Diablo release from the mitochondria and increased levels of XIAP and pro‑caspase 3 in ATP‑depleted HK‑2 cells. In addition, HSP72 interacted with Smac/Diablo. The present data demonstrates that HSP72 preserves renal function in I/R injury through its anti‑apoptotic effects, which act by suppressing mitochondrial Smac/Diablo release and preserving XIAP protein content.
Department of Nephrology, The First Affiliated Hospital, Sun Yat‑sen University, Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, Guangdong 510080, P.R. China.
Baiyu
B
Zhang
Department of Nephrology, The First Affiliated Hospital, Sun Yat‑sen University, Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, Guangdong 510080, P.R. China.
Rong
R
Rong
Department of Nephrology, The First Affiliated Hospital, Sun Yat‑sen University, Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, Guangdong 510080, P.R. China.
Huiyan
H
Li
Department of Nephrology, The First Affiliated Hospital, Sun Yat‑sen University, Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, Guangdong 510080, P.R. China.
Xuan
X
Peng
Department of Nephrology, The First Affiliated Hospital, Sun Yat‑sen University, Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, Guangdong 510080, P.R. China.
Liping
L
Xiong
Laboratory for Kidney Pathology, Inc., Nashville, TN 37203, USA.
Yihan
Y
Wang
Department of Nephrology, The First Affiliated Hospital, Sun Yat‑sen University, Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, Guangdong 510080, P.R. China.
Xueqing
X
Yu
Department of Nephrology, The First Affiliated Hospital, Sun Yat‑sen University, Key Laboratory of Nephrology, Ministry of Health of China, Guangzhou, Guangdong 510080, P.R. China.
Haiping
H
Mao
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D004224:Diterpenes / Q000008:administration & dosage; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019194:Ischemic Preconditioning; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C489013:DIABLO protein, rat; D004224:Diterpenes; D050884:HSP72 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3; C031049:geranylgeranylacetone