Complement-C1q TNF-Related Protein 3 Alleviates Mesangial Cell Activation and Inflammatory Response Stimulated by Secretory IgA.
Elevated circulating IgA complex deposits in the glomerular mesangium and causes resultant mesangial cell activation, eventually leading to the progression of IgA nephropathy (IgAN). Complement-C1q TNF-related protein 3 (CTRP3) is documented as a potential anti-inflammatory and anti-fibrotic mediator; however, its role in IgAN is unknown.



Serum polymeric IgA (pIgA) was isolated from patients with IgAN and healthy volunteers. Human mesangial cells (HMCs) were incubated with the isolated pIgA. The expression of CTRP3 and its effects on inflammatory cytokines and extracellular matrix were evaluated.



Median circulating CTRP3 decreased in patients with IgAN compared to the controls, accompanied by the elevated serum and urine TGF-β and IL-6. While urine CTRP3 in IgAN patients were comparable to that in healthy subjects. pIgA dose-dependently inhibited the expression of CTRP3 and HMC tolerated pIgA at 1.0 mg/ml, for which galactose-deficient IgA might be responsible. pIgA markedly increased IL-6 and TGF-β in HMCs, which were suppressed after Ad-CTRP3 transfection. Additionally, CTRP3 significantly inhibited pIgA-stimulated HMC proliferation, cell cycle progression and synthesis of CTGF and fibronectin. Furthermore, we found that pIgA-treated HMC exhibited higher NF-954;B activity as reflected by the increased levels of nuclear p65. Moreover, Src activation and the subsequent Smad3 phosphorylation were significantly elevated in response to the stimulation with pIgA. However, NF-954;B activity and Smad3 signaling were inhibited after Ad-CTRP3 transfection in HMC.



CTRP3 potentially targeted to NF-954;B and TGF-β-Src-Smad3 signaling and exerted anti-inflammatory and anti-fibrotic roles to attenuate the progression of IgAN, which may represent a new strategy for the treatment of IgAN.
Department of Nephrology, Hainan Medical University Affiliated Hospital, Haikou, China.
Ruicheng
R
Zhang
Liangbao
L
Zhong
Jufeng
J
Zhou
Youming
Y
Peng
D000328:Adult; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005922:Glomerulonephritis, IGA / Q000378:metabolism*; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*
C506069:C1QTNF3 protein, human; D007070:Immunoglobulin A; D016328:NF-kappa B; D048069:Tumor Necrosis Factors; C034639:polymeric IgA