Soluble dipeptidyl peptidase-4 induces epithelial-mesenchymal transition through tumor growth factor-β receptor.

Abstract

Kidney fibrosis is the final manifestation of chronic kidney disease, a condition mainly caused by diabetic nephropathy. Persistent tissue damage leads to chronic inflammation and excessive deposition of extracellular matrix (ECM) proteins. Epithelial-mesenchymal transition (EMT) is involved in a variety of tissue fibrosis and is a process during which epithelial cells transform into mesenchymal-like cells and lose their epithelial functionality and characteristics Dipeptidyl peptidase-4 (DPP4) is widely expressed in tissues, especially those of the kidney and small intestine. DPP4 exists in two forms: a plasma membrane-bound and a soluble form. Serum-soluble DPP4 (sDPP4) levels are altered in many pathophysiological conditions. Elevated circulating sDPP4 is correlated with metabolic syndrome. Because the role of sDPP4 in EMT remains unclear, we examined the effect of sDPP4 on renal epithelial cells. The influences of sDPP4 on renal epithelial cells were demonstrated by measuring the expression of EMT markers and ECM proteins. sDPP4 upregulated the EMT markers ACTA2 and COL1A1 and increased total collagen content. sDPP4 activated SMAD signaling in renal epithelial cells. Using genetic and pharmacological methods to target TGFBR, we observed that sDPP4 activated SMAD signaling through TGFBR in epithelial cells, whereas genetic ablation and treatment with TGFBR antagonist prevented SMAD signaling and EMT. Linagliptin, a clinically available DPP4 inhibitor, abrogated sDPP4-induced EMT. This study indicated that sDPP4/TGFBR/SMAD axis leads to EMT in renal epithelial cells. Elevated circulating sDPP4 levels may contribute to mediators that induce renal fibrosis.