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.

中文翻译：

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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

糖尿病肾病（DKD）是一种严重的糖尿病并发症。虽然在 T2DM 中发现了补体 C5 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 小鼠中测量肾 C5a/C5a 受体 (C5aR) 表达变化。用 C5aR 拮抗剂 (C5aRA) 治疗 Db/db 小鼠，并分析肾功能、肠道微生物群和肾基因组变化。在体外检测了 C5a 和短链脂肪酸 (SCFA) 对信号转导和转录激活因子 3 (STAT3) 通路的影响。C5a 在 T2DM 患者和 db/db 小鼠的肾小球内皮细胞 (GEC) 中上调。尽管糖脂代谢没有改变，但 C5aR 阻断可减轻肾功能障碍、ECM 沉积、db/db 小鼠的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 db/db 小鼠肾脏中许多免疫反应相关基因的表达，例如 STAT3。C5aRA 和 SCFAs 抑制 C5a 诱导的人肾小球内皮细胞 (HRGECs) 中的 STAT3 活化。根据我们的结果，C5 过度活化通过激活 GEC 中的 STAT3 并损害肠肾轴来促进 DKD，这表明这种过度活化是治疗 DKD 的潜在目标。如 STAT3，在 db/db 小鼠肾脏中。C5aRA 和 SCFAs 抑制 C5a 诱导的人肾小球内皮细胞 (HRGECs) 中的 STAT3 活化。根据我们的结果，C5 过度活化通过激活 GEC 中的 STAT3 并损害肠肾轴来促进 DKD，这表明这种过度活化是治疗 DKD 的潜在目标。如 STAT3，在 db/db 小鼠肾脏中。C5aRA 和 SCFAs 抑制 C5a 诱导的人肾小球内皮细胞 (HRGECs) 中的 STAT3 活化。根据我们的结果，C5 过度活化通过激活 GEC 中的 STAT3 并损害肠肾轴来促进 DKD，这表明这种过度活化是治疗 DKD 的潜在目标。