Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham+wild type+placebo; 5/6Nx+ wild type+placebo; 5/6Nx+wild type+linagliptin; sham+knock out+placebo; 5/6Nx+knock out+ placebo; 5/6Nx+knock out+linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin β4 and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-β1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and Glp1r-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1, YB-1, thymosin β4 and TGF-β1) influenced by DPP-4 inhibition.

据报道，二肽基肽酶4型（DPP-4）抑制剂在慢性肾脏疾病的实验模型中具有有益的作用。潜在的机制尚不完全清楚。但是，这些作用可以通过胰高血糖素样肽1（GLP-1）/ GLP-1受体（GLP1R）途径介导。在这里，我们研究了DPP-4抑制剂linagliptin在Glp1r-/-中的肾脏作用用5/6肾切除术（5 / 6Nx）剔除野生型小鼠。将小鼠分为以下组：假+野生型+安慰剂；5 / 6Nx +野生型+安慰剂；5 / 6Nx +野生型+拉格列汀；假+敲除+安慰剂；5 / 6Nx +敲除+安慰剂；5 / 6Nx +敲除+利格列汀。5 / 6Nx引起肾间质纤维化的发展，血浆胱抑素C和肌酐水平显着升高，肾明胶酶/胶原酶，基质金属蛋白酶-1和-13活性受到抑制；利格列汀治疗可抵消野生型和Glp1r-/-的作用老鼠。在各组肾脏中，有298个蛋白质组学信号被差异调节，如质谱法所示，有150个特定于利格列汀治疗的信号。治疗显着上调了源自胶原α-1（I），胸腺素β4和异质核核糖核蛋白A1（HNRNPA1）的三种肽，并显着下调了一种源自Y box结合蛋白-1（YB-1）的肽。蛋白质组学结果使用蛋白质印迹和免疫荧光显微镜进一步证实。同样，5 / 6Nx导致野生型小鼠的肾脏转化生长因子-β1和pSMAD3表达显着上调，而利格列汀明显抵消了野生型和Glp1r-/-的这种上调。老鼠。因此，利格列汀的肾保护作用不能仅归因于GLP-1 / GLP1R途径，突显了受DPP-4影响的其他信号传导途径（胶原I稳态，HNRNPA1，YB-1，胸腺素β4和TGF-β1）的重要性。抑制。