Deguelin Alleviates Renal Tubular Epithelial Cell Injury in Lupus Nephritis by Inhibiting the PI3K/Akt Signaling Pathway

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus. Circadian rhythm disorders are related to the pathogenesis of LN. This study aims to identify the core circadian rhythm–related genes in LN and identify the potential natural active compounds for LN treatment. In the present study, cyclin A2 (CCNA2) and cyclin-dependent kinase inhibitor 3 (CDKN3) were identified as the core targets most related to the circadian rhythm of LN. Both of them were upregulated in blood and kidney tissue samples in LN and had high diagnostic efficacy. Deguelin had strong binding capabilities with CCNA2 and CDKN3 proteins. Deguelin could dose-dependently alleviate lipopolysaccharide-induced human kidney-2 (HK-2) cell damage, inhibit cell apoptosis and the release of inflammatory factors, downregulate the mRNA and protein expression levels of core genes CCNA2 and CDKN3, and inhibit the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The protective effect of deguelin could be reversed by AKT activator SC79 treatment. In summary, CCNA2 and CDKN3 are core genes related to the circadian rhythm in LN. Deguelin probably alleviates renal tubular epithelial cell injury by modulating the expression levels of core genes CCNA2 and CDKN3, inhibiting the activation of the PI3K/Akt signaling pathway, and thus has the potential to become a therapeutic agent for LN.