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Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
Anticancer drug 2-methoxyestradiol protects against renal ischemia/reperfusion injury by reducing inflammatory
Ying-Yin Chen1, Ching-Hua Yeh2, Edmund Cheung So3
1Department of Medical Research, Chi-Mei Medical Center, Tainan 710, Taiwan ; Department of Biotechnology, National Formosa University, Yunlin County 632, Taiwan.
Background:
Ischemia/reperfusion (I/R) injury is a major cause of acute renal failure and allograft dysfunction in kidney transplantation. ROS/inflammatory cytokines are involved in I/R injury. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, inhibits inflammatory cytokine expression and is an antiangiogenic and antitumor agent. We investigated the inhibitory effect of 2ME2 on renal I/R injury and possible molecular actions.
Methods:
BALB/c mice were intraperitoneally injected with 2ME2 (10 or 20 mg/kg) or vehicle 12 h before and immediately after renal I/R experiments. The kidney weight, renal function, tubular damages, and apoptotic response were examined 24 h after I/R injury. The expression of mRNA of interleukin-1β, tumor necrosis factor- (TNF) α, caspase-3, hypoxia inducible factor- (HIF) 1α, and proapoptotic Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) in kidney tissue was determined using RT-PCR, while the expression of nuclear factor κB (NF-κB), BCL-2, and BCL-xL, activated caspase-9, and HIF-1α was determined using immunoblotting. In vitro, we determined the effect of 2ME2 on reactive oxygen species (ROS) production and cell viability in antimycin-A-treated renal mesangial (RMC) and tubular (NRK52E) cells.
Results:
Serum creatinine and blood urea nitrogen were significantly higher in mice with renal I/R injury than in sham control and in I/R+2ME2-treated mice. Survival in I/R+2ME2-treated mice was higher than in I/R mice. Histological examination showed that 2ME2 attenuated tubular damage in I/R mice, which was associated with lower expression TNF-α, IL-1β, caspase-9, HIF-1α, and BNIP3 mRNA in kidney tissue. Western blotting showed that 2ME2 treatment substantially decreased the expression of activated caspase-9, NF-κB, and HIF-1α but increased the antiapoptotic proteins BCL-2 and BCL-xL in kidney of I/R injury. In vitro, 2MR2 decreased ROS production and increased cell viability in antimycin-A-treated RMC and NRK52E cells.
Conclusions:
2ME2 reduces renal I/R injury in mice because it inhibits the expression of ROS and proinflammatory cytokines and induces antiapoptotic proteins.
Insights
2-Methoxyestradiol (2ME2) significantly reduces kidney ischemia/reperfusion (I/R) injury by inhibiting reactive oxygen species (ROS) and inflammatory cytokines, while promoting antiapoptotic proteins. This demonstrates 2ME2
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Ischemia/reperfusion (I/R) injury is a primary cause of acute renal failure and kidney transplant dysfunction.
- Reactive oxygen species (ROS) and inflammatory cytokines play critical roles in I/R injury pathogenesis.
- 2-Methoxyestradiol (2ME2), an endogenous estradiol metabolite, exhibits anti-inflammatory, antiangiogenic, and antitumor properties.
Purpose of the Study:
- To investigate the protective effects of 2ME2 against renal I/R injury in a mouse model.
- To elucidate the underlying molecular mechanisms of 2ME2's action in mitigating I/R-induced kidney damage.
Main Methods:
- Mice were administered 2ME2 (10 or 20 mg/kg) or vehicle before and after inducing renal I/R.
- Kidney function, tubular damage, and apoptosis were assessed 24 hours post-I/R.
- Gene and protein expression of key inflammatory, apoptotic, and hypoxia-related factors (e.g., TNF-α, IL-1β, caspase-9, NF-κB, HIF-1α, Bcl-2) were analyzed.
- In vitro studies evaluated 2ME2's impact on ROS production and cell viability in renal cells.
Main Results:
- 2ME2 treatment significantly improved renal function and survival in I/R mice, evidenced by lower serum creatinine and blood urea nitrogen levels.
- Histological analysis revealed attenuated tubular damage in 2ME2-treated mice.
- 2ME2 administration downregulated the expression of pro-inflammatory cytokines (TNF-α, IL-1β), caspase-9, HIF-1α, and BNIP3, while upregulating antiapoptotic proteins (Bcl-2, Bcl-xL).
- In vitro, 2ME2 reduced ROS production and enhanced cell viability in stressed renal cells.
Conclusions:
- 2-Methoxyestradiol (2ME2) effectively mitigates renal ischemia/reperfusion injury in mice.
- The protective mechanism involves the inhibition of ROS and pro-inflammatory cytokine expression.
- 2ME2 also promotes cell survival by inducing antiapoptotic proteins, highlighting its therapeutic potential for kidney injury.
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