Radish red protects against early diabetic kidney disease through inhibiting inflammation, pyroptosis and insulin resistance via IRAK1 signaling suppression

• Radish red ameliorates renal tubular cells injury. • Radish red reduces lipid deposition and IR in HF-exposed HK2 cells. • Radish red regulates pyroptosis and IRAK1 signaling in HK2 cells under HF stimuli. • Radish red administration ameliorates metabolic dysfunctions in HFF-fed mice. • Radish red ameliorates renal dysfunction and injury in HFF-treated mice. Diabetic kidney disease (DKD) is a major diabetic complication and a leading cause of end-stage renal disease (ESRD), but the therapeutic strategies for DKD are still limited. Red radishes ( Raphanus sativus L.) are a rich source of natural anthocyanins that have antioxidant, anti-apoptotic and anti-inflammatory activities. In this study, we attempted to explore the effects of natural pigment anthocyanin called radish red (RR) extracted from red radishes on DKD progression and the underlying molecular mechanisms. RR dose-dependently reduced the tubular cell injury, indicated by the decreased expression of kidney injury molecule 1 (KIM1). Furthermore, releases of pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) stimulated by HF were strongly relieved by RR. Inflammatory response and pyroptosis were also identified to be induced by HF stimulation but were mitigated by RR in HK2 cells through repressing nuclear factor-κB (NF-κB) activation and NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. IR and lipogenesis due to HF exposure were also significantly ameliorated by RR in HK2 cells. Mechanistically, RNA-Seq analysis showed that RR strongly depressed interleukin-1 receptor-associated kinase-1 (IRAK1)-mediated NLRP3 inflammasome, pyroptosis, IR and lipid deposition. Importantly, IRAK1 overexpression almost diminished the beneficial effects of RR, while being rescued upon NLRP3 knockdown in HF-treated HK2 cells, revealing that RR performed its nephroprotective functions in diabetic kidney via inactivating the IRAK1-NLRP3 signaling pathway. Similarly, animal studies confirmed that RR supplementation efficiently ameliorated HFF-caused metabolic disturbance, IR, renal dysfunctions in mice and improved structural kidney damage. Consistently, RR consumption dramatically reduced lipid accumulation, inflammatory response and pyroptosis in kidney tissues of HFF-challenged mice mainly through repressing IRAK1-NLRP3 axis. Our results demonstrated that dietary supplementation with RR may serve as an IRAK1-NLRP3 inhibitor for preventing and treating diabetic nephropathy.