Protective effect of edaravone on renal-interstitial fibrosis and its mechanism / 解放军医学杂志

ABSTRACT

Objective To observe the effect of edaravone (EDA) on the expressions of malondialdehyde (MDA), phosphorylated extracellular signal-regulated kinase (p-ERK), nuclear factor kappa-B cells (NF-κB) and Collagen-III in rat model of unilateral ureteral obstruction (UUO), and discuss the protective effect of EDA on renal-interstitial fibrosis. Methods Fifty-four male SD rats were randomly divided into three groups (18 each) sham group (normal control), UUO group and EDA group. Rats in UUO group and EDA group received UUO operation. One day before UUO operation, rats in EDA group received intraperitoneal injection of 3.75mg/(kg·d) EDA, and those in sham group and UUO group were injected with equivalent normal saline. Rats were sacrificed in three batches at the 3rd, 7th and 14th day after operation, six from each group in each batch. The renal pathological changes were observed via HE staining and Masson staining. The contents of MDA in renal tissues were determined by spectrophotometry, and the expression levels of p-ERK1/2, NF-κB and collagen-III were detected by immunohistochemistry. Results HE and Masson staining showed no significant changes of MDA content, renal tubules and interstitium in sham group at 3rd, 7th and 14th day, but obvious changes of interstitium and increased fibre deposition in UUO group and EDA group compared with sham group. Compared with UUO group, the lesions of renal tubular and interstitium significantly reduced and the interstitial fibrosis deposition decreased in EDA group. Spectrophotometry indicated that the MDA contents showed no significant difference between EDA group and UUO group [(9.261±0.496)nmol/mg prot and (10.143±0.301)nmol/mg prot] on the 3rd day after operation, but was higher than in sham group [(6.918±1.120)nmol/mg prot]. The MDA contents at the 7th and 14th day after surgery in EDA group [(11.545±0.620)nmol/mg prot and (15.203±0.512)nmol/mg prot] were significantly lower than in UUO group [(13.405±0.612)nmol/mg prot and (18.133±1.684)nmol/mg prot]. Immunohistochemistry analysis showed that no significant difference existed in the expressions of p-ERK1/2, NF-κB and Collagen III at the 3 time points in sham group; At the 3rd day after surgery, the expressions of p-ERK1/2, NF-κB and Collagen III were higher in EDA group (19 055.7±1866.1, 11 217.0±989.9 and 9724.1±341.9) than in sham group (14 100.3±1822.7, 7975.1±2058.5 and 6890.0±2389.9, P0.05). At the 7th and 14th day after surgery, the expression level of p-ERK1/2 was significantly lower in EDA group (26 228.0±523.0 and 30 647.1±583.8) than in UUO group (28 254.9±886.6 and 33 240.3±1330.4); the expression level of NF-κB was obviously lower in EDA group (16 374.4±1045.3 and 21 111.2±1022.5) than in UUO group (18 799.4±357.0 and 27 125.2±2873.3); the expression level of Collagen-III was markedly lower in EDA group (12 470.9±506.1 and 19 615.8±1120.1) than in UUO group (15 049.9±1372.3 and 22 868.9±1889.2), all the differences were of statistical significance (P<0.05). Conclusion Oxidative stress and the signaling pathway of p-ERK1/2 and NF-κB may play a role in the progress of renal interstitial fibrosis (RIF) in UUO rat model, and EDA may have an antifibrosis effect by down-regulating the levels of oxidative stress in kidney tissue and inhibiting the signaling pathway of p-ERK1/2 and NF-κB.