Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1
Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1
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Caspase-11 通过激活 caspase-1 刺激 IL-1β 成熟促进肾纤维化
DOI：
10.1038/s41401-018-0177-5
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发表时间：
2019-06-01
影响因子：
8.2
通讯作者：
Lu, Li-min
中科院分区：
文献类型：
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作者：
Miao, Nai-jun;Xie, Hong-yan;Lu, Li-min
Caspase-11 是病理条件下炎症反应激活的关键上游调节剂。在这项研究中，我们在体内和体外研究了 caspase-11 在白介素 1 β (IL-1 β) 成熟和肾间质纤维化发展中的作用。小鼠遭受单侧输尿管梗阻（UUO）。小鼠用 caspase-11 抑制剂蟠桃内酯（星期三，30 mg/kg/天，ig）治疗 7 天，或用 caspase-11 siRNA（每天 10 nmol/20 g 体重，静脉注射）治疗 14 天。第14天对小鼠实施安乐死，收集其肾组织和血样。我们发现梗阻肾脏的caspase-11水平显着升高，肾小管损伤和间质纤维化明显。 Wed 或 caspase-11 siRNA 治疗显着减轻了 UUO 小鼠的肾纤维化，组织学变化的改善证明了这一点。此外，抑制 caspase-11 显着减弱梗阻肾脏中 caspase-1 的激活、IL-1 β 成熟、转化生长因子 β (TGF-β)、纤连蛋白和 I 型胶原蛋白的表达。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。 IL-1β (20 ng/ml) 处理显着增加细胞中 TGF-β、纤连蛋白和 I 型胶原蛋白的表达。 caspase-11 siRNA 或 Wed 抑制 Ang II 诱导的 TGF-β、纤连蛋白和胶原蛋白 I 的表达。最后，我们利用免疫共沉淀发现 caspase-11 能够与 NRK-52E 细胞中的 caspase-1 相互作用。这些结果表明 caspase-11 参与 UUO 诱导的肾纤维化。梗阻肾脏中 caspase-11 的升高通过刺激 caspase-1 激活和 IL-1 β 成熟来促进肾纤维化。
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-1 beta (IL-1 beta) 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-1 beta maturation, transforming growth factor-beta (TGF-beta), fibronectin, and collagen I expressions in the obstructed kidney. Renal tubular epithelial NRK-52E cells were treated in vitro with angiotensin (Ang, 1 mu mol/L), which stimulated caspase-11 activation and IL-1 beta maturation. Treatment with IL-1 beta (20 ng/ml) significantly increased the expression of TGF-beta, fibronectin, and collagen I in the cells. Ang II-induced expression of TGF-beta, 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-1 beta maturation.