Renoprotective Mechanism of Remote Ischemic Preconditioning Based on Transcriptomic Analysis in a Porcine Renal Ischemia Reperfusion Injury Model.
Ischemic preconditioning (IPC) is a well-known phenomenon in which tissues are exposed to a brief period of ischemia prior to a longer ischemic event. This technique produces tissue tolerance to ischemia reperfusion injury (IRI). Currently, IPC's mechanism of action is poorly understood. Using a porcine single kidney model, we performed remote IPC with renal IRI and evaluated the IPC mechanism of action. Following left nephrectomy, 15 female Yorkshire pigs were divided into three groups: no IPC and 90 minutes of warm ischemia (control), remote IPC immediately followed by 90 minutes of warm ischemia (rIPCe), and remote IPC with 90 minutes of warm ischemia performed 24 hours later (rIPCl). Differential gene expression analysis was performed using a porcine-specific microarray. The microarray analysis of porcine renal tissues identified 1,053 differentially expressed probes in preconditioned pigs. Among these, 179 genes had altered expression in both the rIPCe and rIPCl groups. The genes were largely related to oxidation reduction, apoptosis, and inflammatory response. In the rIPCl group, an additional 848 genes had altered expression levels. These genes were primarily related to immune response and inflammation, including those coding for cytokines and cytokine receptors and those that play roles in the complement system and coagulation cascade. In the complement system, the membrane attack complex was determined to be sublytic, because it colocalized with phosphorylated extracellular signal-regulated kinase. Furthermore, alpha 2 macroglobulin, tissue plasminogen activator, uterine plasmin trypsin inhibitor, and arginase-1 mRNA levels were elevated in the rIPCl group. These findings indicate that remote IPC produces renoprotective effects through multiple mechanisms, and these effects develop over a long timeframe rather than immediately following IPC.
Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Young Eun
YE
Yoon
Department of Urology, CHA Bundang Medical Center, CHA University, Seongnam-si, Korea.
Kyung Hwa
KH
Choi
Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Sook Young
SY
Kim
Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Young In
YI
Cho
Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Kwang Suk
KS
Lee
Department of Urology, Ewha Women's University Mokdong Hospital, Seoul, Korea.
Kwang Hyun
KH
Kim
Department of Urology, CHA Bundang Medical Center, CHA University, Seongnam-si, Korea.
Seung Choul
SC
Yang
Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Woong Kyu
WK
Han
D000818:Animals; D016207:Cytokines / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D019194:Ischemic Preconditioning / Q000379:methods; D007668:Kidney / Q000293:injuries* / Q000378:metabolism*; D009392:Nephrectomy / Q000379:methods; D018121:Receptors, Cytokine / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics*; D013552:Swine; D052096:Warm Ischemia / Q000379:methods
D016207:Cytokines; D018121:Receptors, Cytokine; D048049:Extracellular Signal-Regulated MAP Kinases