1. Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice
- Author
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Ting Gao, Hanning You, Timothy K. Cooper, W. Brian Reeves, Wesley M. Raup-Konsavage, Sarah K. Bronson, and Alaa S. Awad
- Subjects
Male ,0301 basic medicine ,CCR2 ,Chemokine ,animal diseases ,030232 urology & nephrology ,Apoptosis ,Monocytes ,Blood Urea Nitrogen ,Podocyte ,Diabetic nephropathy ,0302 clinical medicine ,Diabetic Nephropathies ,Mice, Knockout ,Kidney ,biology ,Podocytes ,hemic and immune systems ,Up-Regulation ,Phenotype ,medicine.anatomical_structure ,Mice, Inbred DBA ,Nephrology ,Inflammation Mediators ,medicine.symptom ,Signal Transduction ,medicine.drug ,medicine.medical_specialty ,Receptors, CCR2 ,Mice, Transgenic ,Inflammation ,Article ,Collagen Type I ,Streptozocin ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Diabetes mellitus ,Internal medicine ,parasitic diseases ,medicine ,Albuminuria ,Animals ,Genetic Predisposition to Disease ,RNA, Messenger ,business.industry ,Macrophages ,medicine.disease ,Streptozotocin ,Fibrosis ,Fibronectins ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Endocrinology ,biology.protein ,business - 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.
- Published
- 2017