Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Korea.
Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul, South Korea.
Cell Death Dis. 2022 Jan 10;13(1):31. doi: 10.1038/s41419-021-04480-3.
The NLRP3 inflammasome is activated by mitochondrial damage and contributes to kidney fibrosis. However, it is unknown whether PGC-1α, a key mitochondrial biogenesis regulator, modulates NLRP3 inflammasome in kidney injury. Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome, mitochondrial dynamics and morphology, oxidative stress, and cell injury markers were examined in RTECs treated by TGF-β1 with or without Ppargc1a plasmid, PGC-1α activator (metformin), and siPGC-1α. In vivo, adenine-fed and unilateral ureteral obstruction (UUO) mice were treated with metformin. In vitro, TGF-β1 treatment to RTECs suppressed the expressions of PGC-1α and mitochondrial dynamic-related genes. The NLRP3 inflammasome was also activated and the expression of fibrotic and cell injury markers was increased. PGC-1α induction with the plasmid and metformin improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome and cell injury. The opposite changes were observed by siPGC-1α. The oxidative stress levels, which are inducers of the NLRP3 inflammasome, were increased and the expression of TNFAIP3, a negative regulator of NLRP3 inflammasome regulated by PGC-1α, was decreased by TGF-β1 and siPGC-1α. However, PGC-1α restoration reversed these alterations. In vivo, adenine-fed and UUO mice models showed suppression of PGC-1α and TNFAIP3 and dysregulated mitochondrial dynamics. Moreover, the activation of oxidative stress and NLRP3 inflammasome, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by metformin. This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.
NLRP3 炎性体被线粒体损伤激活，并有助于肾脏纤维化。然而，尚不清楚作为关键线粒体生物发生调节剂的 PGC-1α 是否调节肾脏损伤中的 NLRP3 炎性体。从小鼠中分离原代肾小管上皮细胞（RTEC）。用 TGF-β1 处理 RTECs，并用 Ppargc1a 质粒、PGC-1α 激活剂（二甲双胍）和 siPGC-1α 处理，检查 NLRP3 炎性体、线粒体动力学和形态、氧化应激和细胞损伤标志物。在体内，用二甲双胍处理腺嘌呤喂养和单侧输尿管梗阻（UUO）小鼠。在体外，TGF-β1 处理 RTECs 抑制 PGC-1α 和线粒体动力学相关基因的表达。NLRP3 炎性体也被激活，纤维化和细胞损伤标志物的表达增加。用质粒和二甲双胍诱导 PGC-1α 可改善线粒体动力学和形态，并减轻 NLRP3 炎性体和细胞损伤。用 siPGC-1α 观察到相反的变化。氧化应激水平（NLRP3 炎性体的诱导物）增加，TGF-β1 和 siPGC-1α 降低了由 PGC-1α 调节的 NLRP3 炎性体的负调节因子 TNFAIP3 的表达。然而，PGC-1α 恢复逆转了这些改变。在体内，腺嘌呤喂养和 UUO 小鼠模型显示 PGC-1α 和 TNFAIP3 抑制以及线粒体动力学失调。此外，这些小鼠的氧化应激和 NLRP3 炎性体激活以及肾脏纤维化增加。然而，这些变化在用二甲双胍治疗后显著逆转。这项研究表明，通过调节线粒体活力和动力学，PGC-1α 诱导的 NLRP3 炎性体失活可改善肾脏损伤。
