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Diabetic nephropathy (DN) is an important healthcare challenge because it occurs in about 40% of diabetic people and is a main cause end-stage renal disease. Toll like receptor-4 (TLR-4) signaling is involved in DN incidence and progression through its activation by hyperglycemia and hyperglycemia-induced alterations besides its crucial roles in initiating inflammation and fibrosis in kidney. Syringic acid is a natural phenolic acid. It is naturally available in many fruits and vegetables, including swiss chards, grapes and olives. In this study, renoprotective effects of syringic acid, as anti-inflammatory, anti-oxidant and anti-fibrotic natural compound, against experimental DN were investigated. Streptozotocin (45mg/kg) was used in inducing rat model of DN pathogenesis. Renal TLR-4, transforming growth factor β1 (TGFβ1) and interleukin-6 (IL-6) levels were estimated by ELISA technique. Moreover, renal hydroxyproline and collagen content were evaluated using spectrophotometry. Oral administration of syringic acid (50 mg/kg) for 8 weeks succeeded in keeping kidney function evidenced by significant decrease in serum levels of creatinine, blood urea nitrogen (BUN) and decreased urinary protein content. Also, it produced significant increase in renal superoxide dismutase (SOD) activity and significant decline in kidney malondialdehyde (MDA) content. Moreover, it showed significant anti-inflammatory and antifibrotic effects reflected by significant decrease in renal TLR-4, interleukin-6, TGFβ1 and collagen as compared to DN group. Besides, it significantly attenuated DN-induced histopathological deteriorations. In conclusion, syringic acid can …