Luteolin attenuates lupus nephritis by regulating macrophage oxidative stress via HIF-1α pathway

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) and a leading cause of mortality. Luteolin (LUT), a compound found in many vegetables, fruits, and Chinese herbal medicine, has been shown to possess anti-inflammatory, antioxidant, and immunosuppressive properties. However, the mechanisms underlying LUT's potential therapeutic effects on LN remain unclear. In this study, we investigated LUT's antagonistic effects on inflammation and oxidative stress using MRL/lpr mice and H₂O₂-treated macrophages (Raw264.7). Our results indicate that LUT can ameliorate pathological abnormalities and improve renal function in MRL/lpr mice by reducing renal oxidative stress and urinary protein levels. Furthermore, we found that the Hypoxia-inducible factor 1α (HIF-1α) pathway is involved in the process of LUT improving renal injury in lupus mice. Analysis of GEO data confirmed that HIF-1α expression is significantly elevated in the kidneys of LN patients, and our experiments conducted in vitro and in vivo indicate that infiltrating macrophages contribute to the elevated levels of HIF-1α expression in the kidney. By inhibiting HIF-1α expression and oxidative stress in macrophages, LUT can mitigate renal damage caused by infiltrating macrophages. In conclusion, our findings suggest that LUT may serve as a potential therapeutic option for the prevention and treatment of LN by suppressing HIF-1α expression in macrophages.