Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Pharmacol Res. 2021 May;167:105531. doi: 10.1016/j.phrs.2021.105531. Epub 2021 Mar 4.
Contrast-induced acute kidney injury (CI-AKI) is a main cause of hospital-acquired renal failure. Nevertheless, limited measures have been shown to be effective for the treatment of CI-AKI. Here, we demonstrated that αKlotho, which is highly expressed in kidney, has therapeutic activity in CI-AKI. Our data showed that αKlotho expression levels were decreased both in the kidney and serum of CI-AKI mice. Administration of αKlotho protein protected the kidney and HK-2 cells against contrast-induced injury. Mechanistically, αKlotho reduced contrast-induced renal tubular cells pyroptosis by limiting NLRP3 inflammasome activation. Meanwhile, αKlotho up-regulated autophagy via inhibiting the AKT/mTOR pathway and decreased mitochondrial ROS level. Inhibition of autophagy blunted the suppression effect of αKlotho on NLRP3 inflammasome activation and cell pyroptosis in contrast-treated HK-2 cells. Taken together, our data suggest that αKlotho protein protects against CI-AKI through inhibiting NLRP3 inflammasome-mediated pyroptosis, which is likely by promoting autophagy. αKlotho may be a promising therapeutic strategy for CI-AKI.
对比剂诱导的急性肾损伤（CI-AKI）是医院获得性肾衰竭的主要原因。然而，目前已证实的治疗 CI-AKI 的方法有限。在这里，我们证明了高表达于肾脏的αKlotho 在 CI-AKI 中具有治疗活性。我们的数据显示，CI-AKI 小鼠的肾脏和血清中αKlotho 的表达水平均降低。αKlotho 蛋白的给药可保护肾脏和 HK-2 细胞免受对比剂诱导的损伤。在机制上，αKlotho 通过限制 NLRP3 炎性小体的激活来减少对比剂诱导的肾小管细胞细胞焦亡。同时，αKlotho 通过抑制 AKT/mTOR 通路来上调自噬，并降低线粒体 ROS 水平。自噬的抑制削弱了 αKlotho 对对比处理的 HK-2 细胞中 NLRP3 炎性小体激活和细胞焦亡的抑制作用。总之，我们的数据表明，αKlotho 蛋白通过抑制 NLRP3 炎性小体介导的细胞焦亡来保护 CI-AKI，这可能是通过促进自噬来实现的。αKlotho 可能是治疗 CI-AKI 的一种有前途的治疗策略。
