Complement C5 activation promotes type 2 diabetic kidney disease via activating STAT3 pathway and disrupting the gut-kidney axis.
Complement C5 activation promotes type 2 diabetic kidney disease via activating STAT3 pathway and disrupting the gut-kidney axis.
复制标题
补体 C5 激活通过激活 STAT3 通路和破坏肠肾轴促进 2 型糖尿病肾病
DOI：
10.1111/jcmm.16157
复制
发表时间：
2021-01
影响因子：
5.3
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Li L;Wei T;Liu S;Wang C;Zhao M;Feng Y;Ma L;Lu Y;Fu P;Liu J
糖尿病肾病（DKD）是糖尿病的一种严重并发症。虽然在T2 DM中发现了补体C5上调和肠道生态失调，但它们在DKD中的作用尚不清楚。在这里，我们研究了C5在DKD发育期间对肠道微生物群的影响。在T2 DM患者和db/db小鼠中测量肾脏C5 a/C5 a受体（C5 aR）表达变化。用C5 aR拮抗剂（C5 aRA）处理Db/db小鼠，并分析肾功能、肠道微生物群和肾基因组变化。在体外检测了C5 a和短链脂肪酸（SCFAs）对信号转导和转录激活因子3（STAT 3）通路的影响。C5 a在T2 DM患者和db/db小鼠的肾小球内皮细胞（GEC）中上调。虽然糖和脂质代谢没有改变，但C5 aR阻断可减轻db/db小鼠的肾功能不全、ECM沉积、巨噬细胞浸润和促炎因子表达。C5 aRA部分逆转了db/db小鼠肠道微生物群多样性和丰度以及肠道SCFA水平的下降。C5 aRA下调db/db小鼠肾脏中许多免疫应答相关基因的表达，如STAT 3。C5 aRA和SCFAs抑制C5 a诱导的人肾小球内皮细胞（HRGECs）中的STAT 3活化。根据我们的研究结果，C5超活化通过激活GEC中的STAT 3并损害肠-肾轴来促进DKD，这表明这种超活化是治疗DKD的潜在靶点。
Diabetic kidney disease (DKD) is a severe DM complication. While complement C5 up‐regulation and gut dysbiosis are found in T2DM, their roles in DKD are unclear. Here, we investigated the effect of C5 on the gut microbiota during DKD development. Renal C5a/C5a receptor (C5aR) expression changes were measured in T2DM patients and db/db mice. Db/db mice were treated with a C5aR antagonist (C5aRA), and renal function, gut microbiota and renal genome changes were analysed. The effects of C5a and short‐chain fatty acids (SCFAs) on the signal transducer and activator of transcription 3 (STAT3) pathway were examined in vitro. C5a was up‐regulated in glomerular endothelial cells (GECs) of T2DM patients and db/db mice. Although glucose and lipid metabolism were unchanged, C5aR blockade alleviated renal dysfunction, ECM deposition, macrophage infiltration and proinflammatory factor expression in db/db mice. C5aRA partly reversed the declines in gut microbiota diversity and abundance and gut SCFA levels in db/db mice. C5aRA down‐regulated the expression of many immune response‐related genes, such as STAT3, in db/db mouse kidneys. C5aRA and SCFAs suppressed C5a‐induced STAT3 activation in human renal glomerular endothelial cells (HRGECs). Based on our results, C5 hyperactivation promotes DKD by activating STAT3 in GECs and impairing the gut‐kidney axis, suggesting that this hyperactivation is a potential target for the treatment of DKD.
登录
查看更多内容
影响因子：
120.7
作者：
de Boer, Ian H.;Rue, Tessa C.;Hall, Yoshio N.;Heagerty, Patrick J.;Weiss, Noel S.;Himmelfarb, Jonathan
通讯作者：
Himmelfarb, Jonathan
影响因子：
3.7
作者：
Li L;Yin Q;Tang X;Bai L;Zhang J;Gou S;Zhu H;Cheng J;Fu P;Liu F
通讯作者：
Liu F
影响因子：
64.5
作者：
Levy M;Thaiss CA;Zeevi D;Dohnalová L;Zilberman-Schapira G;Mahdi JA;David E;Savidor A;Korem T;Herzig Y;Pevsner-Fischer M;Shapiro H;Christ A;Harmelin A;Halpern Z;Latz E;Flavell RA;Amit I;Segal E;Elinav E
通讯作者：
Elinav E
影响因子：
5.2
作者：
Geurts L;Lazarevic V;Derrien M;Everard A;Van Roye M;Knauf C;Valet P;Girard M;Muccioli GG;François P;de Vos WM;Schrenzel J;Delzenne NM;Cani PD
通讯作者：
Cani PD
影响因子：
19.6
作者：
Arumugam, TV;Shiels, IA;Taylor, SM
通讯作者：
Taylor, SM