Abstract：
The pathogenesis of glomerular diseases is strongly influenced by abnormal extracellular matrix (ECM) deposition in mesangial cells. Dipeptidyl peptidase IV (DPPIV) enzyme family contains DPP8 and DPP9, which are involved in multiple diseases. However, the pathogenic roles of DPP8 and DPP9 in mesangial cells ECM deposition remain unclear. In this study, we observed that DPP8 and DPP9 were significantly increased in glomerular mesangial cells and podocytes in CKD patients compared with healthy individuals, and DPP9 levels were higher in the urine of IgA nephropathy (IgAN) patients than in control urine. Therefore, we further explored the mechanism of DPP8 and DPP9 in mesangial cells and revealed a significant increase in the expression of DPP8 and DPP9 in human mesangial cells (HMCs) following TGF-β1 stimulation. Silencing DPP8 and DPP9 by siRNAs alleviated the expression of ECM-related proteins including collagen Ⅲ, collagen Ⅳ, fibronectin, MMP2, in TGF-β1-treated HMCs. Furthermore, DPP8 siRNA and DPP9 siRNA inhibited TGF-β1-induced phosphorylation of Smad2 and Smad3, as well as the phosphorylation of Akt in HMCs. The findings suggested the inhibition of DPP8/9 may alleviate HMCs ECM deposition induced by TGF-β1 via suppressing TGF-β1/Smad and AKT signaling pathways.
摘要：
肾小球疾病的发病机制受到肾小球系膜细胞中异常细胞外基质（ECM）沉积的强烈影响。二肽基肽酶Ⅳ(DPPIV)酶家族包含DPP8和DPP9介入多种疾病。然而,DPP8和DPP9在肾小球系膜细胞ECM沉积中的致病作用尚不清楚。在这项研究中,我们观察到，与健康个体相比，CKD患者的肾小球系膜细胞和足细胞中DPP8和DPP9显著增加，IgAN患者尿液中DPP9水平高于对照尿液。因此,我们进一步探索了DPP8和DPP9在肾小球系膜细胞中的作用机制，并揭示了TGF-β1刺激后人肾小球系膜细胞（HMC）中DPP8和DPP9的表达显着增加。通过siRNA沉默DPP8和DPP9减轻ECM相关蛋白的表达，包括Ⅳ型胶原，胶原蛋白Ⅲ,纤连蛋白,MMP2，在TGF-β1处理的HMC中。此外，DPP8siRNA和DPP9siRNA抑制TGF-β1诱导的Smad2和Smad3磷酸化以及HMC中Akt的磷酸化。结果表明，抑制DPP8/9可能通过抑制TGF-β1/Smad和AKT信号通路减轻TGF-β1诱导的HMCsECM沉积。
