Kidney Research Laboratory, Division of Nephrology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
Key Laboratory of Transplant Engineering and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, China.
J Cell Mol Med. 2021 Jan;25(2):960-974. doi: 10.1111/jcmm.16157. Epub 2020 Dec 6.
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.
糖尿病肾病（DKD）是一种严重的糖尿病并发症。虽然在 2 型糖尿病（T2DM）中发现了补体 C5 的上调和肠道菌群失调，但它们在 DKD 中的作用尚不清楚。在这里，我们研究了 C5 在 DKD 发展过程中对肠道微生物群的影响。在 T2DM 患者和 db/db 小鼠中测量了肾脏 C5a/C5a 受体（C5aR）表达的变化。用 C5aR 拮抗剂（C5aRA）治疗 db/db 小鼠，并分析肾功能、肠道微生物群和肾脏基因组的变化。在体外研究了 C5a 和短链脂肪酸（SCFAs）对信号转导和转录激活因子 3（STAT3）通路的影响。在 T2DM 患者和 db/db 小鼠的肾小球内皮细胞（GEC）中上调了 C5a。尽管葡萄糖和脂质代谢没有改变，但 C5aR 阻断减轻了 db/db 小鼠的肾功能障碍、细胞外基质沉积、巨噬细胞浸润和促炎因子表达。C5aRA 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。C5aRA 下调了许多免疫反应相关基因的表达，如 db/db 小鼠肾脏中的 STAT3。C5aRA 和 SCFAs 抑制了 C5a 在人肾肾小球内皮细胞（HRGEC）中诱导的 STAT3 激活。基于我们的结果，C5 的过度激活通过激活 GEC 中的 STAT3 并损害肠道-肾脏轴来促进 DKD，这表明这种过度激活是治疗 DKD 的潜在靶点。
