Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice

Abstract

Many clinical studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have renoprotective properties by ameliorating albuminuria and increasing glomerular filtration rate in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) by lowering ectopic lipid accumulation in the kidney. However, the mechanism of GLP-1RAs was hitherto unknown. Here, we conducted an unbiased lipidomic analysis using ultra-high-performance liquid chromatography/electrospray ionization-quadrupole time-of-flight mass spectrometry (UHPLC/ESI-Q-TOF-MS) and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to reveal the changes of lipid composition and distribution in the kidneys of high-fat diet-fed mice after treatment with a long-acting GLP-1RA dulaglutide for 4 weeks. Treatment of dulaglutide dramatically improved hyperglycemia and albuminuria, but there was no substantial improvement in dyslipidemia and ectopic lipid accumulation in the kidney as compared with controls. Intriguingly, treatment of dulaglutide increases the level of an essential phospholipid constituent of inner mitochondrial membrane cardiolipin at the cortex region of the kidneys by inducing the expression of key cardiolipin biosynthesis enzymes. Previous studies demonstrated that lowered renal cardiolipin level impairs kidney function via mitochondrial damage. Our untargeted lipidomic analysis presents evidence for a new mechanism of how GLP-1RAs stimulate mitochondrial bioenergetics via increasing cardiolipin level and provides new insights into the therapeutic potential of GLP-1RAs in mitochondrial-related diseases.

Evaluation of the effects of ezetimibe on albuminuria and kidney fat in individuals with type 2 diabetes and chronic kidney disease

“…SGLT2Is, and apparently also GLP1RAs, offer kidney protection, and both, especially GLP1RAs, induce weight loss, 34 with visceral and ectopic fat loss 16,36–38 . Reductions in kidney‐PF with these agents have recently been detected in several rodent studies, 39–44 as well as one human study 30 . In the latter, treatment with a GLP1RA (liraglutide), relative to placebo, for 26 weeks significantly reduced kidney‐PF, assessed with MRS, among 17 participants with T2D (mean eGFR: 96 mL/min/1.73m 2 ; median UACR: 16 mg/g), even although baseline median kidney‐PF was only around 0.2% 30 …”

Potentials of Natural Antioxidants in Reducing Inflammation and Oxidative Stress in Chronic Kidney Disease

“…Due to its inhibitory effect on protein kinase C (PKC)-β and concurrent amplificatory action on protein kinase A (PKA), Beinaglutide reduced NADPH oxidases activation, leading to a diminished ROS and glycation end-product accumulation in renal glomeruli and tubules [ 140 , 141 ]. The antioxidant effect of GLP-1 is also supported by the enhancement in oxidative stress metabolites, such as NAD+ and adenosine, and cardiolipin essential for mitochondrial metabolism after Semaglutide and Dulaglutide treatment, respectively [ 142 , 143 ]. Reduction in ROS correlated with the lowered urinary albumin/creatinine ratio and alleviated progression in glomerulopathy.…”

Cardiolipin Alterations during Obesity: Exploring Therapeutic Opportunities

“…In parallel, Yeung et al reported that the protective effect of dulaglutide, a glucagon-like peptide-1 receptor agonist, on kidney function of HFD-induced obese mice, is associated with an increased expression of genes involved in cardiolipin synthesis and remodeling such as Crls and Taz , resulting in an increase of cardiolipin content [ 133 ].…”