title: An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes.
abstract: The progression of diabetic nephropathy is associated with an infiltration of macrophages expressing different phenotypes. As classically activated chemokine receptor CCR2+ macrophages are thought to drive tissue inflammation and remodeling, we tested whether blocking CCR2 could reduce intrarenal inflammation and prevent glomerulosclerosis in type 2 diabetes. This was achieved with RO5234444, an orally active small-molecule CCR2 antagonist that blocks ligand binding, its internalization, and monocyte chemotaxis. Male type 2 diabetic db/db mice were uninephrectomized to increase glomerular hyperfiltration to accelerate the development of glomerulosclerosis. From 16 weeks until killing at 24 weeks of age, mice were chow fed with or without admixed antagonist to achieve a trough plasma concentration above IC50 for binding in the mouse. CCR2 blockade reduced circulating monocyte levels, but did not affect total leukocyte or neutrophil numbers, and was associated with a reduction in the number of macrophages and apoptotic podocytes in the glomerulus. This treatment resulted in a higher total number of podocytes, less glomerulosclerosis, reduced albuminuria, and a significantly improved glomerular filtration rate. This successful pre-clinical trial suggests that this antagonist may now be ready for testing in humans with the nephropathy of diabetes mellitus.
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, University of Munich, Germany.
authors.forename: Sufyan G
authors.initials: SG
authors.lastname: Sayyed
authors.forename: Mi
authors.initials: M
authors.lastname: Ryu
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Kulkarni
authors.forename: Holger
authors.initials: H
authors.lastname: Schmid
authors.forename: Julia
authors.initials: J
authors.lastname: Lichtnekert
authors.forename: Sabine
authors.initials: S
authors.lastname: Grüner
authors.forename: Luke
authors.initials: L
authors.lastname: Green
authors.forename: Patrizio
authors.initials: P
authors.lastname: Mattei
authors.forename: Guido
authors.initials: G
authors.lastname: Hartmann
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000284:Administration, Oral; D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D002934:Cinnamates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051437:Renal Insufficiency / Q000517:prevention & control*
chemical_list: C562038:4-(3-(3-chloro-4-fluorophenyl)acryloyl)-1-(3-(4-hydroxy-6-azaspiro(2.5)oct-6-yl)propyl)-3-methylpiperazin-2-one; C515335:Ccr2 protein, mouse; D002934:Cinnamates; D010879:Piperazines; D012333:RNA, Messenger; D054390:Receptors, CCR2