title: Enalapril treatment increases T cell number and promotes polarization towards M1-like macrophages locally in diabetic nephropathy.
abstract: Diabetic nephropathy (DN) is a serious complication of longstanding diabetes affecting up to 30% of all diabetes patients and is the main cause of end-stage kidney disease globally. Current standard treatment e.g. ACE-inhibitors like enalapril merely offers a delay in the progression leading to DN. Herein, we describe in two preclinical models evidence to local effects on the inflammatory signatures after intervention treatment with enalapril which provides enhanced understanding of the mechanism of ACE inhibitors. Enalapril transiently reduced albuminuria in both the db/db and the STZ-induced DN models with established disease, without modulating the HbA1c%. Albuminuria was strongly associated with loss of leukocytes, particularly B cells, but also of sub-populations of macrophages and CD4(+) T cells. The remaining kidney macrophages were polarized into a M2-like sub-population with reduced surface expression of the M1-like macrophage marker CD11c and enhanced expression of galectin-3. Enalapril treatment counteracted the reduction of leukocytes in the diabetic kidney towards levels noted in the non-diabetic kidney. Particularly, a subset of macrophages was increased and a clear expansion of CD4(+) and CD8(+) T cells was observed. However, enalapril failed to modulate the B cell compartment. Interestingly, enalapril treatment resulted in a re-polarization of the macrophages towards a M1-like phenotype characterized by elevated levels of CD11c with moderate down-regulation of the M2 marker galectin-3. The data demonstrate that ACE inhibition in pre-clinical models of DN shows a transient beneficial effect on albuminuria which is unexpectedly associated with restoration of T cells and M1-like macrophages in the kidney.
authors.affiliation: Diabetic Complications Biology, Novo Nordisk Park, DK-2720 Måløv, Denmark.
authors.forename: Helena
authors.initials: H
authors.lastname: Cucak
authors.affiliation: Diabetic Complications Biology, Novo Nordisk Park, DK-2720 Måløv, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Nielsen Fink
authors.affiliation: Translational Pharmacology, Novo Nordisk Park, DK-2720 Måløv, Denmark.
authors.forename: Maiken
authors.initials: M
authors.lastname: Højgaard Pedersen
authors.affiliation: Diabetic Complications Biology, Novo Nordisk Park, DK-2720 Måløv, Denmark. Electronic address: axrd@novonordisk.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosendahl
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000276:immunology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000276:immunology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D004656:Enalapril / Q000008:administration & dosage* / Q000009:adverse effects; D037502:Galectin 3 / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D018655:Lymphocyte Count; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D039521:CD11c Antigen; D037502:Galectin 3; D004656:Enalapril
keywords: Diabetes; Diabetic nephropathy; Drug treatment; Kidney; Macrophages; T cells