Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

• Published in: PloS one Vol. 11; no. 12; p. e0168396
• Main Authors: Bisgaard, Line S, Bosteen, Markus H, Fink, Lisbeth N, Sørensen, Charlotte M, Rosendahl, Alexander, Mogensen, Christina K, Rasmussen, Salka E, Rolin, Bidda, Nielsen, Lars B, Pedersen, Tanja X
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.12.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Antidiabetics; Aorta; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Biochemistry; Biology and Life Sciences; Cardiovascular diseases; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Collagen (type I); Complications and side effects; Cytometry; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Disease Models, Animal; Dosage and administration; Drug therapy; Fibrosis; Flow cytometry; Gene Knockout Techniques; Genotype & phenotype; Health risks; Histology; Homeostasis; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Inflammation; Kidney - drug effects; Kidney - immunology; Kidney - pathology; Kidney diseases; Kidneys; Liraglutide; Liraglutide - administration & dosage; Liraglutide - pharmacology; Low density lipoprotein receptors; Lymphocytes T; Male; Markers; Medicine and Health Sciences; Mice; Monocytes; Nephrectomy; Nephrology; Receptor density; Receptors, LDL - genetics; Research and Analysis Methods; Rodents; Smooth muscle; Studies; Up-Regulation - drug effects; Uremia; Uremia - drug therapy; Uremia - immunology; Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0168396

Chronic kidney disease (CKD) leads to uremia. CKD is characterized by a gradual increase in kidney fibrosis and loss of kidney function, which is associated with a progressive increase in risk of atherosclerosis and cardiovascular death. To prevent progression of both kidney fibrosis and atherosclerosis in uremic settings, insight into new treatment options with effects on both parameters is warranted. The GLP-1 analogue liraglutide improves glucose homeostasis, and is approved for treatment of type 2 diabetes. Animal studies suggest that GLP-1 also dampens inflammation and atherosclerosis. Our aim was to examine effects of liraglutide on kidney fibrosis and atherosclerosis in a mouse model of moderate uremia (5/6 nephrectomy (NX)). Uremic (n = 29) and sham-operated (n = 14) atherosclerosis-prone low density lipoprotein receptor knockout mice were treated with liraglutide (1000 μg/kg, s.c. once daily) or vehicle for 13 weeks. As expected, uremia increased aortic atherosclerosis. In the remnant kidneys from NX mice, flow cytometry revealed an increase in the number of monocyte-like cells (CD68+F4/80-), CD4+, and CD8+ T-cells, suggesting that moderate uremia induced kidney inflammation. Furthermore, markers of fibrosis (i.e. Col1a1 and Col3a1) were upregulated, and histological examinations showed increased glomerular diameter in NX mice. Importantly, liraglutide treatment attenuated atherosclerosis (~40%, p < 0.05) and reduced kidney inflammation in NX mice. There was no effect of liraglutide on expression of fibrosis markers and/or kidney histology. This study suggests that liraglutide has beneficial effects in a mouse model of moderate uremia by reducing atherosclerosis and attenuating kidney inflammation.