Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model
Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model
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DOI：
10.1186/s40360-020-00432-3
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发表时间：
2020-08-12
影响因子：
2.9
通讯作者：
Oya, Mototsugu
中科院分区：
文献类型：
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作者：
Morita, Shinya;Shinoda, Kazunobu;Oya, Mototsugu
背景：环孢素A(CsA)是器官移植中必不可少的免疫抑制剂。然而，它的慢性肾毒性是同种异体移植物长期存活的障碍，而这一障碍尚未克服。CsA肾病肾组织中核因子-kappaB(NF-kappa B)被激活。本研究旨在探讨特异性核因子-kappaB抑制剂脱羟甲氧奎诺米星(DHMEQ)对环孢素A(CsA)肾病大鼠模型的影响。方法：SD大鼠在低盐饮食条件下行5/6肾切除，每日给予CsA(15 mg/kg)，共28天。治疗组同时给予DHMEQ(8 mg/kg)和CsA，每日1次，连续28天，观察其对CsA肾病的影响。结果：DHMEQ明显抑制CsA所致的核因子-kappaB活化和核转位。CsA+DHMEQ组与CsA对照组比较，血清尿素氮水平分别为69+/-6.4vs113.5+/-8.8vs43.1+/-1.1mgdL，P<0.0001；0.0001)，治疗组肌酐清除率恢复(环孢素A+地塞米松与环孢素A对照组分别为2.57±0.09vs1.94+/-0.12vs4.61+/-0.18ml/min/kg，p<；0.0001)。DHMEQ治疗不改变CsA对尿蛋白分泌的抑制作用。DHMEQ可显著抑制CsA慢性肾毒性所致的肾纤维化发展(CsA+DHMEQ vsCsA对照组，13.4+/-7.1vs35.6+/-18.4vs9.4+/-5.4%，p<；0.0001)，这些结果反映了肾功能评价的结果。DHMEQ还可抑制CsA重复给药引起的趋化因子、单核细胞趋化蛋白-1和趋化因子(c-c基序)配体5的表达增加，抑制巨噬细胞和中性粒细胞向肾组织的渗透。结论：DHMEQ联合CsA免疫抑制治疗有利于预防CsA肾毒性的发生。
Background: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-kappa B (NF-kappa B) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity.Methods: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity.Results: DHMEQ significantly inhibited NF-kappa B activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 +/- 6.4 vs 113.5 +/- 8.8 vs 43.1 +/- 1.1 mg/dL, respectively,p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 +/- 0.02 vs 0.91 +/- 0.02 vs 0.49 +/- 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 +/- 0.09 vs 1.94 +/- 0.12 vs 4.61 +/- 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 +/- 7.1 vs 35.6 +/- 18.4 vs 9.4 +/- 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue.Conclusions: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.