PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis

Abstract

Background: NOD-like receptor, pyrin domain containing protein 3 (NLRP3) contributes to inflammation, cell death, and fibrosis in kidney disease. The NLRP3 inflammasome is activated by mitochondrial damage. However, it is unknown whether peroxisomal proliferator-γ coactivator-1α (PGC-1α), a key mitochondrial biogenesis regulator, can modulate NLRP3 inflammasome pathway. Here, I demonstrated that PGC-1α inhibits activation of NLRP3 inflammasome via preserving mitochondrial viability during kidney injury. Methods: Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome pathway, mitochondrial dynamics and morphology, oxidative stress levels, and cell injury markers were examined in RTECs treated with TGF-β1 alone, TGF-β1+PGC-1α activators (metformin and 5-aminoimidazole-4-carboxamide ribonucleotide [AICAR]) or PGC-1α plasmid, and TGF-β1+small interfering-PGC-1α. For animal study, adenine-fed mice and unilateral ureteral obstruction (UUO) mice were treated with PGC-1α activator. Results: In vitro, TGF-β1 treatment to RTECs suppressed the expression levels of PGC-1α and mitochondrial dynamic-related genes. In addition, the NLRP3 inflammasome pathway was activated and the expression levels of fibrotic and apoptotic cell death markers were increased. The indirect and direct expression of PGC-1α with the activators and the plasmid improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome pathway and cell injury. In contrast, these changes were accentuated by PGC-1α knock-down. The oxidative stress levels, which are inducers of the NLRP3 inflammasome after mitochondrial damage, were increased and the expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), which is regulated by PGC-1α and also known as a negative regulator of NLRP3 inflammasome, was decreased by TGF-β1 and PGC-1α knock-down. However, restoration of PGC-1α significantly reversed these alterations. In vivo, adenine- and UUO-induced kidney injury models resulted in decreased expression levels of PGC-1α, TNFAIP3, and mitochondrial dynamics. In addition, the expression levels of oxidative stress, NLRP3 inflammasome pathway, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by treatment of PGC-1α activator. Conclusion: This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.