Radish red attenuates chronic kidney disease in obese mice through repressing oxidative stress and ferroptosis via Nrf2 signaling improvement

Chronic kidney disease (CKD) presents a significant public health concern, with obesity being a prominent contributing factor to kidney disorders by inducing oxidative stress, lipotoxicity, and tubular cell injury. Natural anthocyanins extracted from red radishes (Raphanus sativus L.) exert antioxidant and anti-apoptotic functions. This study aims to employ a novel natural pigment anthocyanin, referred to as radish red (RR) isolated from red radishes, to alleviate obesity-related metabolic disturbances and kidney impairment in a CKD mouse model induced by high-fat and high-fructose diets (HFFD). The in vitro study initially demonstrated that RR treatment significantly mitigated the palmitate acid (PA)-induced injury and cytotoxicity in human tubular epithelial HK2 cells. Subsequently, RR supplementation notably improved obesity and associated metabolic dysfunctions in mice caused by HFFD. Abnormal renal function indices including serum creatinine, blood urea nitrogen (BUN), uric acid (UA), urine protein, albuminuria and urine albumin-to-creatinine ratio (UACR) were detected in HFFD-fed mice, which were effectively alleviated by RR treatment. Histologically, renal tubular cell injury, lipid deposition, tubular dilatation, and renal fibrosis induced by HFFD were markedly improved after RR administration in mice. Furthermore, RR treatment significantly alleviated oxidative stress in HFFD-fed mice, as evidenced by the decreased renal reactive oxygen species (ROS) production, 4-HNE, and NOX4 expression levels. Anti-oxidants such as superoxide dismutase-1 (SOD1), NAD (P) H: quinone oxidoreductase (NQO1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase (GCLC) were highly upregulated in kidney of HFFD-fed mice with RR consumption through improving NFE2-related factor 2 (Nrf2) signaling activation. Furthermore, ferroptosis was identified in the kidneys of HFFD-fed mice, evidenced by the elevated levels of malondialdehyde (MDA), iron content, and lipid peroxidation, along with the decreased expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). These occurrences were significantly mitigated following RR treatment. Mechanistically, we further discovered that the suppressive effects of RR in restricting oxidative stress, ferroptosis, lipid accumulation, and injury of tubular epithelial cells induced by PA were significantly counteracted by Nrf2 knockdown. Collectively, our results demonstrated that dietary supplementation with RR could potentially serve as an efficacious therapeutic modality for the management of obesity-related CKD progression by enhancing Nrf2 activation to impede oxidative stress and ferroptosis.