title: CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice.
abstract: Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.
authors.affiliation: 850 Maude Ave., Mountain View, CA 94043. rberahovich@chemocentryx.com.
authors.forename: Timothy
authors.initials: T
authors.lastname: Sullivan
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Miao
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dairaghi
authors.forename: Antoni
authors.initials: A
authors.lastname: Krasinski
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Bin N
authors.initials: BN
authors.lastname: Zhao
authors.forename: Trageen
authors.initials: T
authors.lastname: Baumgart
authors.forename: Linda S
authors.initials: LS
authors.lastname: Ertl
authors.forename: Andrew
authors.initials: A
authors.lastname: Pennell
authors.forename: Lisa
authors.initials: L
authors.lastname: Seitz
authors.forename: Jay
authors.initials: J
authors.lastname: Powers
authors.forename: Ruiping
authors.initials: R
authors.lastname: Zhao
authors.forename: Solomon
authors.initials: S
authors.lastname: Ungashe
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wei
authors.forename: Landin
authors.initials: L
authors.lastname: Boring
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Tsou
authors.forename: Israel
authors.initials: I
authors.lastname: Charo
authors.forename: Robert D
authors.initials: RD
authors.lastname: Berahovich
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C515334:CCR2 protein, human; C585356:CCX140-B; D054390:Receptors, CCR2; D013449:Sulfonamides
keywords: albuminuria; chemokine; chemokine (C-C motif) receptor 2; hyperglycemia; macrophage