Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus.

AIM: To investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity.

METHODS: Chronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc ) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc ) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment.

RESULTS: Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes ( SREBP-1C , FAS , and SCD-1 ) was decreased, and expression of genes involved in β-oxidation ( CPT-1 and PPAR- α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-α. Coagonist treatment reduced expression of inflammatory ( TNF- α, MCP-1 , and MMP-9 ) and pro-fibrotic ( TGF- β, COL1A1 , and α -SMA ) genes and also improved histological derangement in renal tissue.

CONCLUSION: Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.