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

Abstract

BACKGROUND:

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.

• Authors: Matthew D Giangola, Weng-Lang Yang, Salil R Rajayer, Michael Kuncewitch, Ernesto Molmenti, Jeffrey Nicastro, Gene F Coppa, Ping Wang
• Journal: The Journal of surgical research (J Surg Res) Vol. 199 Issue 2 Pg. 572-9 (Dec 2015) ISSN: 1095-8673 [Electronic] United States
• PMID: 26182998 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• Recombinant Proteins
• growth arrest-specific protein 6

Topics

• Acute Kidney Injury (blood, pathology, prevention & control)
• Animals
• Apoptosis
• Cell Proliferation
• Cytokines (metabolism)
• Drug Evaluation, Preclinical
• Intercellular Signaling Peptides and Proteins (therapeutic use)
• Kidney (metabolism, pathology)
• Kidney Function Tests
• Male
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Recombinant Proteins (therapeutic use)
• Reperfusion Injury (blood, pathology, prevention & control)