Abstract
ObjectiveDiabetic nephropathy (DN) is a serious complication for patients with diabetes mellitus (DM). Emerging evidence suggests that complement C3a is involved in the progression of DN. The aim of this study was to investigate the effect of C3a Receptor Agonist (C3aRA) on DN and its potential mechanism of action in rats with type 2 diabetes mellitus (T2DM).MethodsT2DM was induced in SD rats by a high fat diet (HFD) plus repeated low dose streptozocin (STZ) injections. T2DM rats were treated with vehicle or C3aRA for 8 weeks. Biochemical analysis, HE and PAS stains were performed to evaluate the renal function and pathological changes. Human renal glomerular endothelial cells (HRGECs) were cultured and treated with normal glucose (NG), high glucose (HG), HG+C3a, HG+C3a+C3aRA and HG+C3a+BAY-11-7082 (p-IKBα Inhibitor) or SIS3 (Smad3 Inhibitor), respectively. Real-time PCR, immunofluorescent staining and western blot were performed to detect the mRNA and protein levels, respectively.ResultsT2DM rats showed worse renal morphology and impaired renal function compared with control rats, including elevated levels of serum creatinine (CREA), blood urea nitrogen (BUN) and urine albumin excretion (UACR), as well as increased levels of C3a, C3aR, IL-6, p-IKBα, collagen I, TGF-β and p-Smad3 in the kidney of T2DM rats and C3a-treated HRGECs. In contrast, C3aRA treatment improved renal function and morphology, reduced CREA, UACR and the intensity of PAS and collagen I staining in the kidney of T2DM rats, and decreased C3a, p-IKBα, IL-6, TGF-β, p-Smad3 and collagen I expressions in HRGECs and T2DM rats.ConclusionC3a mediated pro-inflammatory and pro-fibrotic responses and aggravated renal injury in T2DM rats. C3aRA ameliorated T2DN by inhibiting IKBα phosphorylation and cytokine release, and also TGF-β/Smad3 signaling and ECM deposition. Therefore, complement C3a receptor is a potential therapeutic target for DN.
Highlights
Diabetes mellitus (DM) is a major and increasing health problem worldwide [1]
Recent studies have shown that T1DM patients with nephropathy had higher levels of mannose-binding lectin (MBL) [7], and type 2 diabetes mellitus (T2DM) patients with high level of MBL at baseline had a significantly increased risk of developing albuminuria [8], suggesting that the complement system is involved in the progression of Diabetic nephropathy (DN)
T2DM rats showed impaired renal function when compared with the controls, including increased levels of blood urea nitrogen (BUN), CREA and urine albumin excretion (UACR)
Summary
Diabetic nephropathy (DN) is one of the most important causes leading to endstage renal disease, which affects 15–25% of T1DM patients and 30–40% of T2DM patients [2, 3]. Recent studies have shown that T1DM patients with nephropathy had higher levels of mannose-binding lectin (MBL) [7], and T2DM patients with high level of MBL at baseline had a significantly increased risk of developing albuminuria [8], suggesting that the complement system is involved in the progression of DN. We have previously shown that C3a is a pro-fibrotic factor, which can induce epithelial-myofibroblast transdifferentiation (EMT) in human renal proximal tubular epithelial (HK-2) cells via activation of the TGF-b1/CTGF pathway [15]
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