Brazilin attenuates kidney ischemia-reperfusion injury by regulating inflammation, oxidative stress, and mitochondrial dysfunction.

Brazilin, a natural homoisoflavonoid, is the primary bioactive ingredient derived from the bark and heartwood of <i>Caesalpinia sappan</i> L. It has been proven to exhibit multiple biological activities and therapeutic potential in chronic degenerative diseases, fibrotic disorders, inflammatory diseases, and cancers. However, whether it is involved in regulating the pathological process of acute kidney injury (AKI) is not fully understood. This study aimed to elucidate the role and key pharmacological molecular mechanisms of brazilin in AKI. Our data demonstrated that pretreatment with brazilin can significantly reduce the high expression of serum creatinine (Scr), blood urea nitrogen (BUN), and lipocalin-2 (LCN2) in mice exposed to ischemia/reperfusion (I/R) and alleviate kidney histopathological damage. Meanwhile, pretreatment with brazilin can alleviate apoptosis, inflammation, and oxidative stress injury in the kidney tissue cells by partially inhibiting the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammatory pathway or activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway. <i>In vitro</i>, pretreatment with brazilin significantly downregulated pro-apoptotic Bax and upregulated anti-apoptotic Bcl-2 expression in human renal proximal tubular cells (HK-2) subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Besides, it ameliorated mitochondrial dysfunction by enhancing mitochondrial biogenesis and restoring mitochondrial membrane potential. These effects collectively suppressed oxidative stress injury and NLRP3 inflammasome signaling pathway activation. In summary, brazilin exhibits significant protective effects against I/R-induced AKI by attenuating inflammation, oxidative stress and cell apoptosis, and mitochondrial damage. These findings suggest that brazilin holds promise as a potential therapeutic agent for AKI.