|Title:||Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis||Authors:||Chen, Yi-Ting
Wu, Ching Fang
Duffield, Jeremy S
|Keywords:||endothelium; fibroblast; pathophysiology of renal disease and progression; renal fibrosis; TGF-beta; Animals; Cell Differentiation; Cell Proliferation; Fibrosis; Kidney Diseases; Mice; Myofibroblasts; Pericytes; Receptors, Platelet-Derived Growth Factor; Reperfusion Injury; Signal Transduction; Ureteral Obstruction||Issue Date:||Dec-2011||Publisher:||NATURE PUBLISHING GROUP||Source:||Kidney international||Abstract:||
Pericytes are the major source of scar-producing myofibroblasts following kidney injury; however, the mechanisms of this transition are unclear. To clarify this, we examined Collagen 1 (α1)-green fluorescent protein (GFP) reporter mice (pericytes and myofibroblasts express GFP) following ureteral obstruction or ischemia-reperfusion injury and focused on the role of platelet-derived growth factor (PDGF)-receptor (PDGFR) signaling in these two different injury models. Pericyte proliferation was noted after injury with reactivation of α-smooth muscle actin expression, a marker of the myofibroblast phenotype. PDGF expression increased in injured tubules, endothelium, and macrophages after injury, whereas PDGFR subunits α and β were expressed exclusively in interstitial GFP-labeled pericytes and myofibroblasts. When PDGFRα or PDGFRβ activation was inhibited by receptor-specific antibody following injury, proliferation and differentiation of pericytes decreased. The antibodies also blunted the injury-induced transcription of PDGF, transforming growth factor β1, and chemokine CCL2. They also reduced macrophage infiltration and fibrosis. Imatinib, a PDGFR tyrosine kinase inhibitor, attenuated pericyte proliferation and kidney fibrosis in both fibrogenic models. Thus, PDGFR signaling is involved in pericyte activation, proliferation, and differentiation into myofibroblasts during progressive kidney injury. Hence, pericytes may be a novel target to prevent kidney fibrosis by means of PDGFR signaling blockade.
|Appears in Collections:||醫學系|
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