title: Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.|Global Research, Novo Nordisk, Måløv, Denmark.
authors.forename: Line S
authors.initials: LS
authors.lastname: Bisgaard
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Bosteen
authors.affiliation: Global Research, Novo Nordisk, Måløv, Denmark.
authors.forename: Lisbeth N
authors.initials: LN
authors.lastname: Fink
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Sørensen
authors.affiliation: Global Research, Novo Nordisk, Måløv, Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosendahl
authors.affiliation: Global Research, Novo Nordisk, Måløv, Denmark.
authors.forename: Christina K
authors.initials: CK
authors.lastname: Mogensen
authors.affiliation: Global Research, Novo Nordisk, Måløv, Denmark.
authors.forename: Salka E
authors.initials: SE
authors.lastname: Rasmussen
authors.affiliation: Global Research, Novo Nordisk, Måløv, Denmark.
authors.forename: Bidda
authors.initials: B
authors.lastname: Rolin
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tanja X
authors.identifier: http://orcid.org/0000-0003-2515-3022
authors.initials: TX
authors.lastname: Pedersen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D055786:Gene Knockout Techniques; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000069450:Liraglutide / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D011973:Receptors, LDL / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects; D014511:Uremia / Q000188:drug therapy* / Q000276:immunology
chemical_list: D007004:Hypoglycemic Agents; D011973:Receptors, LDL; D000069450:Liraglutide