Glucagon-like peptide-1 receptor agonist, dulaglutide, ameliorates kidney function in diet-induced obese mice by regulating lipids and metabolites.

Abstract

Obesity is associated with metabolic syndromes, which lead to dyslipidaemia, hyperglycaemia, and ectopic lipid accumulation. Metabolic syndromes increase the risk of type-2 diabetes mellitus (T2DM) and contributes to the development of diabetic kidney disease (DKD). Dulaglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist drug used for glycaemic control in diabetic patients. Multiple assessments of weekly administration of dulaglutide in diabetes (AWARD) randomized clinical trials have shown beneficial effects in kidney function, including a reduction of composite renal outcomes; however, the pharmacological mechanism is still not clear. In this study, a high-fat diet-induced obese mouse model with kidney dysfunction was established. These mice were subsequently treated with dulaglutide for 4 weeks, then measurements were made to assess its renoprotective effects. An untargeted lipidomics analysis using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was developed and performed to obtain lipidome profiles of the kidneys after dulaglutide treatment. Dulaglutide-treated mice showed improvement in metabolic disorders, including improved glucose tolerance and reduction in body weight. In the kidney of the treated mice, there is a reduction in albuminuria. Further morphological examinations showed that the increased capsular space, thickening of the basement membrane and increased ectopic lipid accumulation were ameliorated after the treatment. A multivariate analysis on the kidney lipidome was performed and 65 differential compounds of interest, which are involved in glycerophospholipid metabolism, sphingolipid metabolism and ether lipid metabolism, were identified after the treatment. Ultra-high-performance liquid chromatography-quadrupole time-of­-flight mass spectrometry (UHPLC/ESI-QTOF-MS) and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry imaging (MALDI-MSI) results showed in the kidney cortex region an overall increase in cardiolipin (CL), which is a part of glycerophospholipid metabolism. CL is involved in the structural integrity of mitochondria complexes and essential for normal electron transport function to generate energy for cellular function. Our results have demonstrated that dulaglutide may play a role in renoprotective effects in high-fat diet-induced obese mice with kidney dysfunction. The current study has shed light for understanding the mechanism of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists on DKD via an unbiased untargeted lipidomics approach.