FOXC1 Aggravates the Ischemia-Reperfusion Induced Injury in Renal Tubular Epithelial Cells by Activating NF-κB/NLRP3 Signaling

Renal ischemia-reperfusion injury (RIRI) is a condition characterized by inflammation and cell damage in the kidneys following a period of ischemia and subsequent reperfusion, which lacks effective treating method in the clinic. Exploring molecular mechanisms holds profound significance in guiding the clinical prevention and treatment of RIRI. Herein, the potential function of Forkhead box C1 (FOXC1), a protein belongs to FOX family, in I/R-induced injury in renal tubular epithelial cells (RTECs) was studied to explore potential targets for RIRI. FOXC1 was upregulated in RIRI rats, expressions of which were elevated as time prolonged. FOXC1-overexpressed or knockdown HK-2 cells were constructed, followed by I/R stimulation. FOXC1 was found markedly upregulated in I/R-stimulated HK-2 cells. Notably repressed cell viability, enhanced apoptosis, increased release of inflammatory cytokines, boosted reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and inactivated superoxide dismutase (SOD) enzyme were observed in I/R-stimulated HK-2 cells, which were sharply reversed by silencing FOXC1 and aggravated by overexpression FOXC1. Furthermore, largely increased levels of NLRP3, caspase-1, GSDMD-N, IL-18, IL-1β, and p-p65/p65 were observed in I/R-stimulated HK-2 cells, which were notably suppressed by silencing FOXC1 and further elevated by overexpression FOXC1. Additionally, FOXC1-overexpressed HK-2 cells were stimulated by I/R with or without 10 μM MCC950, an inhibitor of NLRP3. The enhanced apoptosis, triggered inflammation, and facilitated ROS by FOXC1 overexpression in I/R-stimulated HK-2 cells were remarkably abolished by the coculture of MCC950, accompanied by an inhibition on the NF-κB/NLRP3 signaling. Collectively, FOXC1 aggravated the I/R induced injury in RTECs by activating NF-κB/NLRP3 signaling.