ABSTRACT
BACKGROUND: Tissue fibrosis and microvascular rarefaction are hallmarks of progressive renal disease. CD248 is a transmembrane glycoprotein expressed by key effector cells within the stroma of fibrotic kidneys including pericytes, myofibroblasts and stromal fibroblasts. In human disease, increased expression of CD248 by stromal cells predicts progression to end-stage renal failure. We therefore, hypothesized that the genetic deletion of the CD248 gene would protect against fibrosis following kidney injury. METHODS: Using the unilateral ureteral obstruction (UUO) model of renal fibrosis, we investigated the effect of genetic deletion of CD248 on post obstructive kidney fibrosis. RESULTS: CD248 null mice were protected from fibrosis and microvascular rarefaction following UUO. Although the precise mechanism is not known, this may to be due to a stabilizing effect of pericytes with less migration and differentiation of pericytes toward a myofibroblast phenotype in CD248-/- mice. CD248-/- fibroblasts also proliferated less and deposited less collagen in vitro. CONCLUSION: These studies suggest that CD248 stromal cells have a pathogenic role in renal fibrosis and that targeting CD248 is effective at inhibiting both microvascular rarefaction and renal fibrosis through modulation of pericyte and stromal cell function.
Subject(s)
Antigens, Neoplasm/metabolism , Kidney Diseases/genetics , Kidney Diseases/pathology , Kidney/pathology , Stromal Cells/physiology , Animals , Antigens, Neoplasm/genetics , Fibrosis , Kidney/chemistry , Male , Mice , Mice, Knockout , Pericytes/physiology , Receptors, Platelet-Derived Growth Factor/physiology , Stromal Cells/chemistryABSTRACT
The systemic vasculitides are a group of diseases where the primary pathological process is inflammatory injury to blood vessel walls. Their clinical manifestations are highly variable and range from organ specific disease to a systemic illness that can lead, if untreated, to multi-organ failure and death. The kidneys are often involved in systemic vasculitis, particularly in small vessel vasculitis, where the glomerular capillary bed is a target for injury. This leads to a vasculitic glomerulonephritis, with focal segmental inflammation and perivascular leukocyte accumulation evolving to extracapillary accumulation of mononuclear cells (including crescents). The kinetics of leukocyte infiltration and involvement in this setting are in part dependent on the combinatorial expression of chemokines and their receptors. We discuss the evidence base for the role of the chemokine network in the renal disease of small vessel vasculitis and extend this to non-renal aspects of small vessel vasculitis other systemic vasculitides.
