title: Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice.
abstract: Inflammation is a central pathophysiologic mechanism that contributes to diabetes mellitus and diabetic nephropathy. Recently, we showed that macrophages directly contribute to diabetic renal injury and that pharmacological blockade or genetic deficiency of chemokine (C-C motif) receptor 2 (CCR2) confers kidney protection in diabetic nephropathy. However, the direct role of CCR2 in kidney-derived cells such as podocytes in diabetic nephropathy remains unclear. To study this, we developed a transgenic mouse model expressing CCR2 specifically in podocytes (Tg[NPHS2-Ccr2]) on a nephropathy-prone (DBA/2J) and CCR2-deficient (Ccr2-/-) background with heterozygous Ccr2+/-littermate controls. Diabetes was induced by streptozotocin. As expected, absence of CCR2 conferred kidney protection after nine weeks of diabetes. In contrast, transgenic CCR2 overexpression in the podocytes of Ccr2-/-mice resulted in significantly increased albuminuria, blood urea nitrogen, histopathologic changes, kidney fibronectin and type 1 collagen expression, podocyte loss, and glomerular apoptosis after nine weeks of streptozotocin-induced diabetes. Interestingly, there was no concurrent increase in kidney macrophage recruitment or inflammatory cytokine levels in the mice. These findings support a direct role for CCR2 expression in podocytes to mediate diabetic renal injury, independent of monocyte/macrophage recruitment. Thus, targeting the CCR2 signaling cascade in podocytes could be a novel therapeutic approach for treatment of diabetic nephropathy.
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Hanning
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Gao
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Wesley M
authors.initials: WM
authors.lastname: Raup-Konsavage
authors.affiliation: Department of Comparative Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Bronson
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: W Brian
authors.initials: WB
authors.lastname: Reeves
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA; Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania, USA. Electronic address: asa17@psu.edu.
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013311:Streptozocin; D015854:Up-Regulation
chemical_list: C515335:Ccr2 protein, mouse; D024042:Collagen Type I; D005353:Fibronectins; D018836:Inflammation Mediators; D012333:RNA, Messenger; D054390:Receptors, CCR2; D013311:Streptozocin
keywords: CCR2; diabetic nephropathy; podocytes