Objective To investigate the therapeutic effect of icariin on diabetic kidney disease (DKD) and elucidate its molecular mechanism from the perspective of renal inflammatory response and related inflammatory signaling pathways. Methods A DKD model was established using C57BL/KsJ db/db mice, with age-matched db/m mice on the same genetic background serving as control group. The db/db mice were randomly divided into model group, dapagliflozin (1.6 mg/kg) group, icariin high-, medium-, low-dose (120, 60, 30 mg/kg) groups, with 10 mice in each group. Drugs were given for continuously intervention over four weeks, biochemical parameters including body weight, blood glucose, urinary protein, blood lipids and serum creatinine were measured. Renal pathological changes were observed using hematoxylin-eosin staining and transmission electron microscopy. The expressions of extracellular matrix proteins [fibronectin (FN) and collagen type IV (Col-Ⅳ)] in the glomerular mesangium was assessed by immunofluorescence. Levels of inflammatory cytokines [interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α)] and proteins related to high mobility group box 1 (HMGB1)/Toll-like receptors (TLRs)/nuclear factor-κB (NF-κB) signaling pathway were detected by ELISA assay and Western blotting. In vitro experiments were performed to investigate the effect of icariin on extracellular matrix protein expressions in high glucose-induced SV40 MES-13 cells. Results In vivo experiments results showed that high-dose icariin significantly reduced the body weight, urinary protein, blood lipid and serum creatinine levels in DKD mice (P < 0.01, 0.001), alleviated pathological changes such as mesangial expansion, basement membrane thickening and podocyte fusion (P < 0.001), reduced the levels of IL-1β, IL-6 and TNF-α in plasma and renal tissue (P < 0.01, 0.001), decreased the infiltration of macrophages in the kidney, and significantly inhibited the protein expressions of HMGB1, TLR2, TLR4 and p-p65 in renal tissue (P < 0.001). In vitro experiments results showed that icariin inhibited the expressions of FN and Col-Ⅳ in high glucose-induced glomerular mesangial cells. Conclusion Icariin could effectively inhibit HMGB1/TLRs/NF-κB signaling pathway, thereby attenuating renal inflammatory response and abnormal extracellular matrix accumulation, ultimately improving pathological injury in DKD.

diabetic kidney disease  /  icariin  /  inflammatory response  /  HMGB1/TLRs/NF-κB signaling pathway  /  extracellular matrix