Glucagon-like peptide-1 agonists alleviate adenine-induced nephrotoxicity in rats: interaction with the renin-angiotensin system and role of NLRP-3 inflammasome, nephrin and KIM-1

Abstract

Chronic kidney disease (CKD) is a devastating health problem with increasing prevalence owing to many factors, among which is the rise in metabolic disorders, such as type 2 diabetes. Recent years have seen the development of several therapeutic tools with a significant impact on diabetes complications. The present study aimed to investigate the possible renoprotective effect of glucagon-like peptide-1 receptor agonists (GLP-1RA), in a rat model of adenine-induced CKD, together with its potential interaction with the underlying pathological activation of the renin-angiotensin system (RAS). Computational assessment showed significant interactions among GLP-1 and GLP-1RA with components of RAS and inflammatory cascades within the context of CKD. For validation, twenty-five male Wistar rats were divided as follows: normal, CKD, and CKD treated with ramipril, liraglutide, or both. The CKD group developed significant perturbations in serum renal function parameters in addition to renal structural deterioration. This was accompanied by pathological changes in renal molecular expression profiles indicative of inflammation and apoptosis. Oxidative stress parameters aligned with the inflammatory changes. Treatment with liraglutide or ramipril equivalently improved renal function and ameliorated changes in renal structural and molecular profiles overall, albeit with slight variations in different parameters. Nevertheless, the combination of both treatments consistently showed superior effects to either treatment alone, supporting the possibility that GLP-1RA might affect more than one target in the RAS cascade. The present results warrant future investigation of the possible therapeutic effect of GLP-1RA in the context of CKD or CKD risk conditions associated with increased RAS activity.