1. Academic Validation
  2. 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

  • J Cell Mol Med. 2021 Jan;25(2):960-974. doi: 10.1111/jcmm.16157.
Ling Li 1 Tiantian Wei 1 Shuyun Liu 2 Chengshi Wang 2 Meng Zhao 2 Yanhuan Feng 1 Liang Ma 1 Yanrong Lu 2 Ping Fu 1 Jingping Liu 2
Affiliations

Affiliations

  • 1 Kidney Research Laboratory, Division of Nephrology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
  • 2 Key Laboratory of Transplant Engineering and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, China.
Abstract

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.

Keywords

SCFA; STAT3; complement C5; diabetic kidney disease; gut microbiota; inflammation.

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