The impact of the glucagon-like peptide 1 receptor agonist liraglutide on the streptozotocin-induced diabetic mouse kidney proteome

Abstract

In diabetes mellitus ( DM ), the kidneys are exposed to increased levels of hyperglycemia‐induced oxidative stress. Elevated amounts of reactive oxygen species ( ROS ) are believed to provoke ultrastructural changes in kidney tissue and can eventually result in DM late complications such as diabetic nephropathy. While it is reported that glucagon‐like peptide 1 receptors ( GLP ‐1R) are present in the kidney vasculature, the effects of GLP ‐1 on the kidney proteome in DM is not well described. Thus, we set out to investigate potential effects on the proteomic level. Here the effects of GLP ‐1R agonism using the GLP ‐1 analogue liraglutide are studied in the kidneys of streptozotocin ( STZ )‐treated mice ( n = 6/group) by label‐free shotgun mass spectrometry ( MS ) and targeted MS . Unsupervised and supervised multivariate analyses are followed by one‐way ANOVA . Shotgun MS data of vehicle and liraglutide‐treated mouse groups are separated in the supervised multivariate analysis and separation is also achieved in the subsequent unsupervised multivariate analysis using targeted MS data. The mouse group receiving the GLP ‐1R agonist liraglutide has increased protein abundances of glutathione peroxidase‐3 ( GPX 3) and catalase ( CATA ) while the abundances of neuroplastin ( NPTN ) and bifunctional glutamate/proline– tRNA ligase ( SYEP ) are decreased compared to the STZ vehicle mice. The data suggest that GLP ‐1R agonism mainly influences abundances of structurally involved proteins and proteins involved in oxidative stress responses in the STZ mouse kidney. The changes could be direct effects of GLP ‐1R agonism in the kidneys or indirectly caused by a systemic response to GLP ‐1R activation.

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

“…revealed that liraglutide attenuates oxidative stress and albuminuria in streptozotocin (STZ)-diabetic rats via the PKA-mediated inhibition of renal NADPH oxidases ( Hendarto et al., 2012 ). Liljedahl et al performed label-free shotgun mass spectrometry (MS) and demonstrated that liraglutide increased the abundance of structurally involved proteins as well as proteins involved in oxidative stress responses in the kidney of STZ-induced diabetic mice ( Liljedahl et al., 2019 ). Moreover, it is reported that exendin-4 inhibits mesangial fibrotic responses ( Li et al., 2012 ; Xu et al., 2014 ).…”

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

“…In the in vivo experiment, the improved cardiomyocyte viability and increased autophagic flux were parallel with significantly decreased myocardial fibrosis and on a functional level with improved cardiac function as assessed by echocardiography [ 89 ]. The same molecular mechanisms resulting in the promotion of autophagy were also demonstrated in cultured hepatocytes and in the in vivo model of high-fat diet-fed C57BL/6 mice in which liraglutide significantly reduced the degree of liver steatosis [ 90 ]. In both cited experiments, chloroquine (an inhibitor of autophagy) promoted heart and liver injury, and these effects were also prevented by liraglutide [ 117 , 118 ].…”

“…The authors observed that STZ injection led to a significantly decreased content of catalase and glutathione peroxidase-3, enzymes critically involved in tissue protection against oxidative stress. The abundance of both enzymes was restored when animals with STZ-induced diabetes were concomitantly treated with liraglutide [ 90 ].…”

Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent

“…Exendin-4 therapy resulted in a substantial reduction in all these lesions ( 167 ). In another similar mouse model, liraglutide resulted in restoration of catalase and glutathione peroxidase-3 levels, enzymes crucial in tissue protection against oxidative damage in kidneys ( 168 ).…”