Growth arrest-specific protein 6 protects against renal ischemia-reperfusion injury

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• 作者：Matthew D. Giangola ; MD^a ; Weng-Lang Yang ; PhD^a ; ^b ; Salil R. Rajayer ; MD^b ; Michael Kuncewitch ; MD^a ; Ernesto Molmenti ; MD^a ; Jeffrey Nicastro ; MD^a ; Gene F. Coppa ; MD^a ; Ping Wang ; MD^a ; ^b ; ^{pwang@nshs.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Gas6 ; Renal ; Ischemia ; Reperfusion ; Inflammation ; Apoptosis ; Proliferation
• 刊名：Journal of Surgical Research
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：199
• 期：2
• 页码：572-579
• 全文大小：1379 K

文摘

Renal injury caused by ischemia–reperfusion (I/R) often occurs after shock or transplantation. Growth arrest–specific protein 6 (Gas6) is a secreted protein that binds to the TAM—Tyro3, Axl, Mer—family tyrosine kinase receptors, which modulate the inflammatory response and activate cell survival pathways. We hypothesized that Gas6 could have a protective role in attenuating the severity of renal injury after I/R.

Materials and methods

Adult mice were subjected to 45 min of bilateral renal ischemia. Recombinant mouse Gas6 (rmGas6, 5 μg per mouse) or normal saline (vehicle) was administered intraperitoneally 1 h before ischemia and all subjects were sacrificed at 23 h after I/R for blood and tissue analysis. The expression of protein and messenger RNA (mRNA) was assessed by Western blotting and quantitative polymerase chain reaction, respectively.

Results

Treatment with rmGas6 significantly decreased serum levels of creatinine and blood urea nitrogen by 29% and 27%, respectively, improved the renal histologic injury index, and reduced the apoptosis in the kidneys, compared with the vehicle. Renal mRNA levels of interleukin 1β, interleukin 6, tumor necrosis factor α, keratinocyte-derived chemokine and macrophage inflammatory protein 2 were decreased significantly by 99%, 60%, 53%, 58%, and 43%, with rmGas6 treatment, respectively. After I/R, renal I-kappa-B α levels were reduced by 40%, whereas they returned to sham levels with rmGas6 treatment. The mRNA levels of inducible nitric oxide synthase and cyclooxygenase 2 were reduced by 79% and 70%, respectively, whereas the expression of cyclin D1 was increased by 2.1-fold in the rmGas6-treated group, compared with the vehicle.

Conclusions

Gas6 suppresses the nuclear factor κB pathway and promotes cell proliferation, leading to the reduction of inflammation and protection of renal injury induced by I/R.