C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway.
C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway.
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DOI：
10.1371/journal.pone.0113639
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Li L;Yin Q;Tang X;Bai L;Zhang J;Gou S;Zhu H;Cheng J;Fu P;Liu F
糖尿病肾病（DN）是糖尿病（DM）患者的严重并发症。新的证据表明，补体C3 a参与DN的进展。本研究旨在探讨C3 a受体激动剂（C3 aRA）对2型糖尿病（T2 DM）大鼠DN的影响及其可能的作用机制。通过高脂饮食（HFD）加重复低剂量链脲佐菌素（STZ）注射在SD大鼠中诱导T2 DM。用媒介物或C3 aRA处理T2 DM大鼠8周。采用生化分析、HE及PAS染色观察肾功能及病理改变。培养人肾小球内皮细胞（HRGECs），分别用正常葡萄糖（NG）、高糖（HG）、HG + C3 a、HG + C3 a + C3 aRA、HG+ C3 a +BAY-11-7082（p-IKBα Inhibitor）或SIS 3（Smad 3 Inhibitor）处理。采用实时荧光定量PCR、免疫荧光染色和western blot方法分别检测mRNA和蛋白水平。与对照组相比，T2 DM大鼠肾脏形态学和肾功能均明显受损，包括血清肌酐（CREA）、血尿素氮（BUN）和尿白蛋白排泄（UACR）水平升高，以及T2 DM大鼠肾脏和C3 a处理的HRGECs中C3 a、C3 aR、IL-6、p-IKBα、I型胶原、TGF-β和p-Smad 3水平升高。C3 aRA可改善T2 DM大鼠肾功能和形态，降低T2 DM大鼠肾脏CREA、UACR、PAS和I型胶原染色强度，降低HRGECs和T2 DM大鼠C3 a、p-IKBα、IL-6、TGF-β、p-Smad 3和I型胶原表达。C3 a介导了促炎和促纤维化反应，并加重了T2 DM大鼠的肾损伤。C3 aRA通过抑制IKBα磷酸化和细胞因子释放，以及TGF-β/Smad 3信号转导和ECM沉积来改善T2 DN。因此，补体C3 a受体是DN潜在的治疗靶点。
Diabetic 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). T2DM 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. T2DM 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. C3a 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.
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影响因子：
3.2
作者：
Maezawa Y;Takemoto M;Yokote K
通讯作者：
Yokote K
DOI：
10.1152/ajprenal.90601.2008
发表时间：
2009-05
期刊：
American journal of physiology. Renal physiology
影响因子：
--
作者：
Satchell SC;Braet F
通讯作者：
Braet F
影响因子：
16.2
作者：
American Diabetes Association
通讯作者：
American Diabetes Association
影响因子：
3.6
作者：
Jinnin, M;Ihn, H;Tamaki, K
通讯作者：
Tamaki, K
影响因子：
8.2
作者：
Hansen, T. K.;Forsblom, C.;Groop, P. -H.
通讯作者：
Groop, P. -H.