title: C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease.
abstract: BACKGROUND
  Endothelial-myofibroblast transition (EndMT) has been implicated in the pathogenesis of diabetic renal fibrosis. In this study, the effect of the complement fragments C3a/C5a and their receptor antagonists C3aRA and C5aRA on EndMT in diabetic kidney disease (DKD) and the possible mechanisms were investigated.
  
  
  METHODS
  The coexpression of CD31 with α-smooth muscle (α-SMA), C3a receptor (C3aR) and C5a receptor (C5aR) was detected in human renal biopsy tissue obtained from patients with early and advanced DKD and in normal renal tissues from patients with renal-cell carcinoma. The effects of C3aRA and C5aRA on EndMT and the expression of C3a/C3aR, C5a/C5aR, α-SMA, CD31, TGFβ, FN and β-catenin were examined in a streptozotocin (STZ)-induced rat model of DKD and in human renal glomerular endothelial cells (HRGECs) cultured in high glucose and with C3a/C5a, and DKK1 (a Wnt/β-catenin inhibitor).
  
  
  RESULTS
  Double-labeling of α-SMA, C3aR, C5aR and CD31 was detected in the glomerulus of renal tissues obtained from biopsies of patients with DKD. Upregulated expression of α-SMA, TGF-β, FN and β-catenin and downregulated expression of CD31 were detected in the GECs of diabetic rats. The expression of these proteins was inhibited by treatment with C3aRA/C5aRA. In vitro, C3aRA/C5aRA and DKK1 ameliorated the high glucose-induced EndMT and the subsequent expression of α-SMA, TGFβ, FN and β-catenin in HRGECs.
  
  
  CONCLUSIONS
  The blockade of C3aR/C5aR and the downstream Wnt/β-catenin pathway may prevent EndMT and alleviate fibrosis in the glomeruli of individuals with DKD.
authors: Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Ling
authors: L
authors: Li
authors: Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Lijia
authors: L
authors: Chen
authors: Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Jing
authors: J
authors: Zang
authors: Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Xi
authors: X
authors: Tang
authors: Laboratory Animal Center of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Yan
authors: Y
authors: Liu
authors: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Jie
authors: J
authors: Zhang
authors: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Lin
authors: L
authors: Bai
authors: Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Qinghua
authors: Q
authors: Yin
authors: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Yanrong
authors: Y
authors: Lu
authors: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Jingqiu
authors: J
authors: Cheng
authors: Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
authors: Ping
authors: P
authors: Fu
authors: Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: liufangfh@163.com.
authors: Fang
authors: F
authors: Liu
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D015926:Complement C3a / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: C488033:C5AR1 protein, human; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D051155:Wnt1 Protein; C085567:complement C3a receptor; D015926:Complement C3a; D015936:Complement C5a
keywords: C3a receptor antagonists; C5a receptor antagonists; Diabetic kidney disease; Endothelial-myofibroblast transition; Wnt/β-catenin signaling pathway