The impact of liraglutide on the JAK-STAT pathway in diabetic kidney disease in db/db mice and in cultured endothelial cells.

BACKGROUND: Emerging evidence demonstrates the involvement of Janus kinase/signal transducer and transcription activator (JAK/STAT) proteins in the pathophysiology of diabetic kidney disease (DKD). The JAK/STAT pathway is involved in the inflammatory response and endothelial cell dysfunction observed in DKD. The GLP-1 analogue, liraglutide, is an effective treatment for type 2 diabetes mellitus, as it improved the inflammatory changes observed in experimental models of DKD. This study used db/db mice and endothelial cells (EC) to determine the effect of diabetic environment on the JAK-STAT pathway and to assess the potential effect of liraglutide in both models.

METHODS: Diabetic db/db mice, 12-weeks-old, were treated with liraglutide for 14 weeks. The kidneys were then perfused and removed for mRNA, protein and immunohistochemistry analysis. EC were stimulated with advanced glycation end products (AGEs), glucose and liraglutide for 24 hours. Total RNA and protein were extracted and analyzed for expression of JAK-STAT signaling.

RESULTS: Phospho (p)-STAT3 was significantly up-regulated in db/db mice compared to non-diabetic mice. Liraglutide significantly down-regulated p-STAT3 protein expression. p-STAT3 was mainly expressed in the glomeruli, while p-JAK2 was also expressed in the kidney tubules. In EC, liraglutide treatment prevented increased expression of p-STAT3 and p-JAK2. Liraglutide inhibited the target gene SOCS3 and SIRT1 in db/db mice and in cultured EC.

CONCLUSION: This study suggests that GLP-1 analogue inhibits the JAK-STAT pathway that participates in intracellular processes in experimental models of diabetes. This article is protected by copyright. All rights reserved.