title: C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway.
abstract: OBJECTIVE
  Diabetic nephropathy (DN) is a serious complication for patients with diabetes mellitus (DM). Emerging evidence suggests that complement C3a is involved in the progression of DN. The aim of this study was to investigate the effect of C3a Receptor Agonist (C3aRA) on DN and its potential mechanism of action in rats with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  T2DM was induced in SD rats by a high fat diet (HFD) plus repeated low dose streptozocin (STZ) injections. T2DM rats were treated with vehicle or C3aRA for 8 weeks. Biochemical analysis, HE and PAS stains were performed to evaluate the renal function and pathological changes. Human renal glomerular endothelial cells (HRGECs) were cultured and treated with normal glucose (NG), high glucose (HG), HG+C3a, HG+C3a+C3aRA and HG+C3a+BAY-11-7082 (p-IKBα Inhibitor) or SIS3 (Smad3 Inhibitor), respectively. Real-time PCR, immunofluorescent staining and western blot were performed to detect the mRNA and protein levels, respectively.
  
  
  RESULTS
  T2DM rats showed worse renal morphology and impaired renal function compared with control rats, including elevated levels of serum creatinine (CREA), blood urea nitrogen (BUN) and urine albumin excretion (UACR), as well as increased levels of C3a, C3aR, IL-6, p-IKBα, collagen I, TGF-β and p-Smad3 in the kidney of T2DM rats and C3a-treated HRGECs. In contrast, C3aRA treatment improved renal function and morphology, reduced CREA, UACR and the intensity of PAS and collagen I staining in the kidney of T2DM rats, and decreased C3a, p-IKBα, IL-6, TGF-β, p-Smad3 and collagen I expressions in HRGECs and T2DM rats.
  
  
  CONCLUSIONS
  C3a mediated pro-inflammatory and pro-fibrotic responses and aggravated renal injury in T2DM rats. C3aRA ameliorated T2DN by inhibiting IKBα phosphorylation and cytokine release, and also TGF-β/Smad3 signaling and ECM deposition. Therefore, complement C3a receptor is a potential therapeutic target for DN.
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Tang
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Bai
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Shenju
authors.initials: S
authors.lastname: Gou
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Hongping
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015926:Complement C3a / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000150:complications / Q000503:physiopathology*; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011951:Receptors, Complement / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D011951:Receptors, Complement; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D015926:Complement C3a; D051550:I-kappa B Kinase