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Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-10-31 , DOI: 10.1038/s41401-018-0177-5 Nai-Jun Miao 1 , Hong-Yan Xie 1 , Dan Xu 1 , Jian-Yong Yin 2 , Yan-Zhe Wang 3 , Bao Wang 1 , Fan Yin 1 , Zhuan-Li Zhou 1 , Qian Cheng 1 , Pan-Pan Chen 1 , Li Zhou 1 , Hong Xue 1 , Wei Zhang 1 , Xiao-Xia Wang 2 , Jun Liu 1 , Li-Min Lu 1
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-10-31 , DOI: 10.1038/s41401-018-0177-5 Nai-Jun Miao 1 , Hong-Yan Xie 1 , Dan Xu 1 , Jian-Yong Yin 2 , Yan-Zhe Wang 3 , Bao Wang 1 , Fan Yin 1 , Zhuan-Li Zhou 1 , Qian Cheng 1 , Pan-Pan Chen 1 , Li Zhou 1 , Hong Xue 1 , Wei Zhang 1 , Xiao-Xia Wang 2 , Jun Liu 1 , Li-Min Lu 1
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Caspase-11 is a key upstream modulator for activation of inflammatory response under pathological conditions. In this study, we investigated the roles of caspase-11 in the maturation of interleukin-1β (IL-1β) and development of renal interstitial fibrosis in vivo and in vitro. Mice were subjected to unilateral ureteral obstruction (UUO). The mice were treated with either caspase-11 inhibitor wedelolactone (Wed, 30 mg/kg/day, ig) for 7 days or caspase-11 siRNA (10 nmol/20 g body weight per day, iv) for 14 days. The mice were euthanized on day 14, their renal tissue and blood sample were collected. We found that the obstructed kidney had significantly higher caspase-11 levels and obvious tubular injury and interstitial fibrosis. Treatment with Wed or caspase-11 siRNA significantly mitigated renal fibrosis in UUO mice, evidenced by the improved histological changes. Furthermore, caspase-11 inhibition significantly blunted caspase-1 activation, IL-1β maturation, transforming growth factor-β (TGF-β), fibronectin, and collagen I expressions in the obstructed kidney. Renal tubular epithelial NRK-52E cells were treated in vitro with angiotensin (Ang, 1 μmol/L), which stimulated caspase-11 activation and IL-1β maturation. Treatment with IL-1β (20 ng/ml) significantly increased the expression of TGF-β, fibronectin, and collagen I in the cells. Ang II-induced expression of TGF-β, fibronectin, and collagen I were suppressed by caspase-11 siRNA or Wed. Finally, we revealed using co-immunoprecipitation that caspase-11 was able to interact with caspase-1 in NRK-52E cells. These results suggest that caspase-11 is involved in UUO-induced renal fibrosis. Elevation of caspase-11 in the obstructed kidney promotes renal fibrosis by stimulating caspase-1 activation and IL-1β maturation.
中文翻译：
Caspase-11通过激活caspase-1刺激IL-1β成熟，从而促进肾纤维化。
Caspase-11是在病理条件下激活炎症反应的关键上游调节剂。在这项研究中，我们研究了caspase-11在白介素1β（IL-1β）的成熟和体内和体外肾间质纤维化发展中的作用。小鼠受到单侧输尿管梗阻（UUO）。小鼠用caspase-11抑制剂韦德尔内酯（Wed，30 mg / kg / day，ig）治疗7天或caspase-11 siRNA（10 nmol / 20 g体重每天，iv）治疗14天。在第14天对小鼠实施安乐死，收集其肾脏组织和血液样本。我们发现阻塞的肾脏具有明显更高的caspase-11水平，并具有明显的肾小管损伤和间质纤维化。使用Wed或caspase-11 siRNA处理可显着减轻UUO小鼠的肾纤维化，组织学改变的改善证明了这一点。此外，caspase-11抑制显着减弱了阻塞性肾脏中caspase-1的激活，IL-1β的成熟，转化生长因子-β（TGF-β），纤连蛋白和胶原蛋白I的表达。肾小管上皮NRK-52E细胞在体外用血管紧张素（Ang，1μmol/ L）处理，刺激caspase-11激活和IL-1β成熟。用IL-1β（20 ng / ml）处理可显着增加细胞中TGF-β，纤连蛋白和胶原蛋白I的表达。caspase-11 siRNA或Wed抑制了Ang II诱导的TGF-β，纤连蛋白和胶原I的表达。最后，我们使用免疫共沉淀法揭示了caspase-11能够与NRK-52E细胞中的caspase-1相互作用。这些结果表明，胱天蛋白酶11参与UUO诱导的肾纤维化。
更新日期：2019-01-26
中文翻译：
Caspase-11通过激活caspase-1刺激IL-1β成熟，从而促进肾纤维化。
Caspase-11是在病理条件下激活炎症反应的关键上游调节剂。在这项研究中，我们研究了caspase-11在白介素1β（IL-1β）的成熟和体内和体外肾间质纤维化发展中的作用。小鼠受到单侧输尿管梗阻（UUO）。小鼠用caspase-11抑制剂韦德尔内酯（Wed，30 mg / kg / day，ig）治疗7天或caspase-11 siRNA（10 nmol / 20 g体重每天，iv）治疗14天。在第14天对小鼠实施安乐死，收集其肾脏组织和血液样本。我们发现阻塞的肾脏具有明显更高的caspase-11水平，并具有明显的肾小管损伤和间质纤维化。使用Wed或caspase-11 siRNA处理可显着减轻UUO小鼠的肾纤维化，组织学改变的改善证明了这一点。此外，caspase-11抑制显着减弱了阻塞性肾脏中caspase-1的激活，IL-1β的成熟，转化生长因子-β（TGF-β），纤连蛋白和胶原蛋白I的表达。肾小管上皮NRK-52E细胞在体外用血管紧张素（Ang，1μmol/ L）处理，刺激caspase-11激活和IL-1β成熟。用IL-1β（20 ng / ml）处理可显着增加细胞中TGF-β，纤连蛋白和胶原蛋白I的表达。caspase-11 siRNA或Wed抑制了Ang II诱导的TGF-β，纤连蛋白和胶原I的表达。最后，我们使用免疫共沉淀法揭示了caspase-11能够与NRK-52E细胞中的caspase-1相互作用。这些结果表明，胱天蛋白酶11参与UUO诱导的肾纤维化。
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