Fibrocyte: New participant in the pathogenesis of renal fibrosise

Abstract

Progressive fibrosis is a common pathological finding in various organs, resulting in organ failure. Renal fibrosis is a progressive disease caused by diverse clinical entities. Irrespective and independent of the primary lesion, it is the severity of renal fibrosis that correlates best with the loss of renal function and the risk for progression to renal failure. A circulating population of cells (termed fibrocytes) that display leukocyte markers such as CD45 and CD34 as well as mesenchymal markers including type I collagen has been described. Fibrocytes have been reported to rapidly enter sites of tissue injury and contribute to the pathogenesis of fibrotic conditions. Fibrocytes express CCR7 and migrate in response to secondary lymphoid tissue chemokine (SLC/CCL21). We hypothesized that CCR7-positive fibrocytes contribute to renal fibrosis. To investigate this idea, renal fibrosis was induced by unilateral ureteral obstruction in mice. CD45- and type I collagen-dual positive fibrocytes infiltrated in the fibrotic kidneys and the number of infiltrated fibrocytes increased with the progression of the extent of fibrosis in an experimental murine renal fibrosis model. Most infiltrated fibrocytes in the kidneys were positive for CCR7. In addition, CCL21 protein co-localized with high endothelial venulelike vessels in fibrotic kidneys. The blockade of CCL21/CCR7 signaling reduced the number of infiltrating fibrocytes as well as the extent of renal fibrosis, which was confirmed by the reduction of the amount of hydroxyproline and the levels of renal transcripts of pro α1 chain of type I collagen and transforming growth factor-β1. These results suggest that CCR7-positive fibrocytes infiltrate into the kidney via CCL21-positive vessels, thereby, contributing to the pathogenesis of renal fibrosis. Thus, regulating the recruitment and activation of fibrocytes by modulation of CCL21/CCR7 signaling may provide a novel therapeutic approach for combatting organ fibrosis.