The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis

Mar 14, 2018Pharmacological research

The diabetes drug liraglutide reduces kidney scarring

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Abstract

Liraglutide treatment reduced collagen deposition and the expression of fibrosis-related markers in a rat model of chronic kidney disease.

Unilateral ureteral obstruction (UUO) led to increased collagen deposition and upregulation of fibronectin and collagen type I alpha 1 in kidney tissues.
Liraglutide-treated UUO mice showed blunted collagen deposition and reduced mRNA expression of fibrosis markers compared to control mice.
Epithelial-mesenchymal transition (EMT) was indicated by increased levels of Snail1 and alpha smooth muscle actin, and decreased E-cadherin in UUO kidneys, which were improved with liraglutide treatment.
Liraglutide treatment decreased the expression of TGF-β1 and its receptor, inhibiting the activation of signaling pathways associated with fibrosis.
In vitro, TGF-β1 induced EMT and extracellular matrix secretion in renal tubular epithelial cells, effects that were mitigated by liraglutide.
The protective effects of liraglutide were negated by a GLP-1 receptor antagonist, indicating the importance of GLP-1 receptor activation in its therapeutic action.

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Renal fibrosis is recognized as the common route of all chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Additionally, accumulating evidence suggests that epithelial-mesenchymal transition (EMT) plays a significant role in the process of renal fibrogenesis. Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been widely used to treat type 2 diabetes. Recent studies have demonstrated that the GLP-1 analogs could also exert protective effects in cardiac fibrosis models. However, the effects of liraglutide on the progression of CKD remain largely unknown. In the present study, we investigated the effects of liraglutide on the progression to renal fibrosis induced by unilateral ureteral obstruction (UUO) and EMT of rat renal tubular epithelial cells (NRK-52E) induced with recombinant transforming growth factor-beta 1 (TGF-β1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1α1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (α-SMA), and downregulation of E-cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-β1 and its receptor (TGF-β1R) and inhibited the activation of its downstream signaling molecules (pSmad3 and pERK1/2). The in vitro results showed that the EMT and extracellular matrix (ECM) secretion of NRK-52E cells were induced by TGF-β1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-β1. All these effects were attenuated by liraglutide treatment. However, the protective effects of liraglutide were abolished by co-incubation of the GLP-1 receptor (GLP-1R) antagonist exendin-3 (9-39). These results suggest that liraglutide attenuates the EMT and ECM secretion of NRK-52E cells induced by TGF-β1 and EMT and renal fibrosis induced by UUO. The potential mechanism involves liraglutide binding to and activating GLP-1R, which prevents EMT by inhibiting the activation of TGF-β1/Smad3 and ERK1/2 signaling pathways, thereby decreasing the ECM secretion and deposition. Therefore, liraglutide is a promising therapeutic agent that may halt the progression of renal fibrosis.

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The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis

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