Glucagon-Like Peptide-1 Mediates the Protective Effect of the Dipeptidyl Peptidase IV Inhibitor on Renal Fibrosis via Reducing the Phenotypic Conversion of Renal Microvascular Cells in Monocrotaline-Treated Rats

Figure 6

Dipeptidyl peptidase-4 (DPP-4) inhibition with sitagliptin decreases the degranulation of glucagon-like peptide-1 (GLP-1) 7-36 (active form) and promotes the transduction of GLP-1R signalling, which can be blocked by the GLP-1R antagonist exendin-3. The GLP-1R agonist liraglutide can activate GLP-1R signalling directly. In smooth muscle cells (SMCs), the activation of GLP-1R upregulates the expression of smooth muscle 22 alpha (SM22α), which is expressed at high levels in the contractile phenotype of SMCs, and inhibits the transition of SMCs from the contractile phenotype to the synthetic phenotype. The extracellular matrix derived from the synthetic phenotype of SMCs is then obviously reduced. In endothelial cells, activated GLP-1R signalling can upregulate bone morphogenetic protein receptor type 2 (BMPR2) expression and reduce transforming growth factor-β1 (TGF-β1)/Smad3 signalling, followed by inhibiting Snail expression. Then, the protein expression of endothelial marker von Willebrand factor (vWF) increases, while that of the mesenchymal marker α-smooth muscle actin (αSMA) decreases. After that, the endothelial-mesenchymal transition (EndMT) programme is blocked, the extracellular matrix derived from myofibroblasts is reduced, and, ultimately, renal fibrosis is attenuated.