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Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
Growth arrest-specific protein 6 protects against renal ischemia-reperfusion injury
Matthew D Giangola1, Weng-Lang Yang2, Salil R Rajayer3
1Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York.
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.
Insights
Growth arrest-specific protein 6 (Gas6) protects against kidney injury from ischemia-reperfusion (I/R). Gas6 treatment reduced inflammation and apoptosis, improving kidney function and histology in mice.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Renal ischemia-reperfusion (I/R) injury is a significant clinical challenge, often occurring post-shock or transplantation.
- Growth arrest-specific protein 6 (Gas6) is a key ligand for TAM receptors, known to regulate inflammation and cell survival.
- The potential protective role of Gas6 in mitigating I/R-induced renal damage was investigated.
Purpose of the Study:
- To evaluate the therapeutic potential of Gas6 in a mouse model of renal ischemia-reperfusion injury.
- To elucidate the molecular mechanisms underlying Gas6-mediated protection against kidney damage.
Main Methods:
- Adult mice underwent 45 minutes of bilateral renal ischemia.
- Recombinant mouse Gas6 (rmGas6) was administered intraperitoneally 1 hour pre-ischemia.
- Kidney injury, inflammation markers, apoptosis, and relevant gene/protein expression (Western blot, qPCR) were assessed 23 hours post-I/R.
Main Results:
- rmGas6 treatment significantly reduced serum creatinine and blood urea nitrogen levels.
- Histological analysis showed improved renal injury scores and reduced apoptosis in rmGas6-treated mice.
- rmGas6 significantly downregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and NF-κB pathway activation, while upregulating cell proliferation markers.
Conclusions:
- Gas6 exhibits significant renoprotective effects against ischemia-reperfusion injury.
- Gas6 suppresses the nuclear factor-κB (NF-κB) pathway, reducing inflammation and promoting cell survival.
- These findings highlight Gas6 as a promising therapeutic agent for preventing or treating renal I/R injury.
