Background: Renal fibrosis is a prevention and treatment target for chronic kidney disease(CKD) including diabetic nephropathy (DN). Objective: The aim of this study was to determine whether low-molecular-weight fucoidan (LMWF) can reduce harmful transforming growth factor β (TGF-β)-mediated the pathogenesis of tubulointerstital fibrosis in DN using in vitro and in vivo experimental models. Materials and methods: Type I diabetes was induced in male Sprague-Dawley rats via intraperitoneal injection of Streptozotocin (STZ; 65 mg/kg). GK rat, a nonobese, normotensive model of non–insulin-dependent diabetes was used as type Ⅱ diabetes model, and Wistar rat was used as control. LMWF was administered to the diabetic rats at a daily dose of 100 mg/kg body weight by intragastric administration. Following 12 weeks treatment, we measured body and kidney weight, blood glucose, blood pressure, creatinine and urea concentration in serum and urine, urine output, urinary osmolality, urinary protein excretion. α-SMA, E-cadherin, fibronectin, TGF-β1, CTGF were measured by Western blot to evaluate the level of epithelial-to-mesenchymal transition (EMT). Results: 10 ng/ml TGF-β1 induced EMT and activated downstream pathways in HK2 cells. The treatment of LMWF significantly reversed EMT and dose-dependently inhibited accumulation of extracellular matrix proteins, including connective tissue growth factor and fibronectin. In type 1 and type 2 diabetic rat models, it was found that diabetes resulted in TGF-β signaling activation and increased expression of TGF-β downstream signals in kidneys. LMWF significantly reduced blood urea nitrogen (28.1 mg/dl) and blood creatinine (89.6 μM) compared with untreated type 1 diabetic group (37.4 mg/dl and 123.3 μM respectively). LMWF also significantly reduced BUN (23.3 mg/dl) and blood creatinine (86.3 μM) compared with untreated type 2 diabetic group (30.4 mg/dl and 111.6 μM respectively). Conclusions: It was also found that LMWF treatment may protect kidney from dysfunction and fibrogenesis in diabetic rat models by inhibiting TGF-β pathway. The experimental results showed that LMWF reduced TGF-β-mediated cell responses in renal interstitial fibrosis, which suggests the potential benefit of LMWF to slow down the progression of DN.

Key words: TGF-β; epithelial-mesenchymal transition (EMT); diabetic nephropathy (DN); fibrogenesis; renal interstitial fibrosis