Liraglutide Improves the Kidney Function in a Murine Model of Chronic Kidney Disease

Abstract

<b><i>Background:</i></b> Chronic kidney disease (CKD) is a global health burden, and the current treatment options only slow down the disease progression. GLP-1 receptor agonists (GLP-1 RA) have shown a renal protective effect in models of CKD; however, the mechanism behind the beneficial effect is not understood. In this study, we investigate the effect of the GLP-1 RA liraglutide in the nephrotoxic serum nephritis (NTN) CKD model. Moreover, we compare the gene expression pattern of liraglutide-treated mice to the gene expression pattern of mice treated with the angiotensin converting enzyme inhibitor, enalapril. <b><i>Methods:</i></b> The effect of liraglutide was tested in the NTN model by evaluating the glomerular filtration rate (GFR), albuminuria, mesangial expansion, renal fibrosis, and renal inflammation. Furthermore, the regulation of selected genes involved in CKD and in glomerular, cortical tubulointerstitial, and whole kidney structures was analyzed using a gene expression array on samples following laser capture microdissection. <b><i>Results:</i></b> Treatment with liraglutide improved CKD hallmarks including GFR, albuminuria, mesangial expansion, renal inflammation, and renal fibrosis. The gene expression revealed that both liraglutide and enalapril reversed the regulation of several fibrosis and inflammation associated genes, which are also regulated in human CKD patients. Furthermore, liraglutide and enalapril both regulated genes in the kidney involved in blood pressure control. <b><i>Conclusions:</i></b> Treatment with liraglutide improved the kidney function and diminished renal lesions in NTN-induced mice. Both liraglutide and enalapril reversed the regulation of genes involved in CKD and regulated genes involved in blood pressure control.

A Hypercaloric Diet Induces Early Podocyte Damage in Aged, Non-Diabetic Rats

“…In other studies, liraglutide was proven to act in an anti-inflammatory, anti-fibrotic and renoprotective manner [19,21,[45][46][47]. Here, we found a significant increase in CD44 and CD68 positive inflammatory cells and a more pronounced tubulointerstitial fibrosis in the HFHCD+liraglutide treated group compared to the HFHCD group.…”

Activation of the renal GLP‐1R leads to expression of Ren1 in the renal vascular tree

“…Hence, it could be speculated that liraglutide treatment can act locally in the kidney to induce angiotensin II cleavage and hence upregulation of the angiotensin 1-7/mas1 pathway. 33 This explanation is supported by an increase in angiotensin 1-7 levels found in diabetic rats following liraglutide treatment. 38 Angiotensin 1-7 activation of the g-protein coupled receptor Mas1 mediate tissue protective processes including anti-inflammatory signalling, reduction in fibrosis, and increased endothelial signalling.…”

“…The Mas1 gene codes for the receptor of angiotensin 1‐7, the peptide arising from angiotensin II following proteolytic processing by angiotensin converting enzyme 2. Hence, it could be speculated that liraglutide treatment can act locally in the kidney to induce angiotensin II cleavage and hence upregulation of the angiotensin 1‐7/mas1 pathway 33 . This explanation is supported by an increase in angiotensin 1‐7 levels found in diabetic rats following liraglutide treatment 38 .…”

“…Other downstream mediators of the renin recruitment effect may be factors belonging to the RAAS system. From preclinical and clinical studies RAAS inhibitors are known to decrease fibrosis, inflammation and albuminuria, 33–35 but they also lead to renin recruitment 36,37 . In this context, GLP‐1RA’s have previously shown effects on the regulation of components of RAAS independently of haemodynamic effects.…”

Liraglutide restores late cardioprotective effects of remote preconditioning in diabetic rats via activation of hydrogen sulfide and nuclear factor erythroid 2-related factor 2 signaling pathway

“…It is also been increasingly used to manage weight in obese people 8 with potential weight loss benefits, approved for the treatment of type 2 diabetes (T2D. Apart from it, liraglutide has been shown to exert neuroprotective effect and preserve cognitive functions 9 , decrease renal fibrosis 10 and improve heart contractility 11 and decrease heart remodeling 12 . There are important mediators revealed by different scientists that are important in inducing cardioprotective effects of remote preconditioning.…”