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

Martin Ho Yin Yeung,Lai Yuen Choi,Jung Sun Yoo,Susan Yung,Ka Long Leung,Pui-Kin So,Chi-Ming Wong

doi:10.3389/fphar.2021.777395

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.

Highlights

Diabetic kidney disease (DKD) is one of the most serious progressive complications commonly observed in humans with diabetes (Yu and Bonventre, 2018)
We presented the evidence that dulaglutide protects renal function by elevating the level of a unique mitochondrial inner membrane phospholipid, cardiolipin, in the kidney cortex region via the upregulation of the mRNA expression of cardiolipin synthesis enzymes, which leads to alleviation of overnutrition-impaired kidney mitochondrial bioenergetics
Previous studies demonstrated that GLP-1RAs could be utilized in treating DKD in humans (Marso et al, 2016a; Marso et al, 2016b; Muskiet et al, 2018; Tuttle et al, 2018; Gerstein et al, FIGURE 3 | Bioinformatics analysis of lipidomics of the kidneys of standard chow control (STC), high-fat diet-induced diabetic nephropathy (HFD) and H + Dula groups (A–F) The score plots from principal component analysis (PCA), PLS-DA and orthogonal partial least-squared discriminant analysis (OPLS-DA) model between the HFD and the H + Dula group

Summary

INTRODUCTION

Diabetic kidney disease (DKD) is one of the most serious progressive complications commonly observed in humans with diabetes (Yu and Bonventre, 2018). Until recently, accumulating evidence from clinical and experimental studies demonstrated that the glycemic control drugs, glucagonlike-peptide-1 receptor agonists (GLP-1RAs), are effective and safe glycemic control drugs for diabetic patients with kidney disease (Edwards and Minze, 2015; Coskun et al, 2018). GLP-1RAs reduced glycation end products, leading to lowered inflammation in renal mesangial cells (Chang et al, 2017). Reducing renal lipotoxicity can inhibit the development of DKD-associated pathologies by resensitizing podocytes to insulin signaling in DKD mouse models (Falkevall et al, 2017). It remains unclear whether these renoprotective properties are a direct effect of GLP-1RAs on kidney lipid metabolism or an indirect effect of improvements in overall metabolic syndromes. We presented the evidence that dulaglutide protects renal function by elevating the level of a unique mitochondrial inner membrane phospholipid, cardiolipin, in the kidney cortex region via the upregulation of the mRNA expression of cardiolipin synthesis enzymes, which leads to alleviation of overnutrition-impaired kidney mitochondrial bioenergetics

MATERIALS AND METHODS

RESULTS

ETHICS STATEMENT