Winning Abstracts from the 2011 Medical Student Abstract Competition: CXCL16 Plays A Critical Role In Renal Fibrosis Through Regulation Of Bone Marrow-Derived Fibrocytes
Author: Joseph George Maliakkal, Baylor College of Medicine, Class of 2011
Introduction: Chronic kidney disease is a growing public health problem and renal fibrosis is a prominent pathological feature of CKD. Although fibroblasts are responsible for the production and deposition of the extracellular matrix in renal fibrosis, the origin of fibroblasts mediating renal fibrosis has been controversial. Recent evidence indicates that circulating CD45+ collagen I+ fibroblast precursors, termed fibrocytes, contribute to the pathogenesis of renal fibrosis. However, the signaling mechanisms responsible for the recruitment of bone marrow-derived fibrocytes into the kidney are incompletely understood. In this study, we investigated the role of CXCL16 in the recruitment of bone marrow-derived fibrocytes into the kidney and its role in renal fibrosis in a well-established model of tubulointerstitial injury induced by unilateral ureteral obstruction (UUO) using CXCL16 knockout mice.
Methods: Wild-type and CXCL16 knockout mice were subjected to UUO for up to 2 weeks. Renal cells were isolated using enzymatic digestion and flow cytometry was performed to quantify the number of fibrocytes in the kidney. Picrosirius red staining was done to evaluate the degree of renal fibrosis. Real time RT-PCR, immunohistochemistry and Western blot analysis were performed to determine the levels of collagen I, fibronectin, and alpha-SMA in the kidney.
Results: Our results revealed that CD45 and collagen I dual positive fibrocytes progressively accumulated in the injured kidney of wild-type mice, reaching a peak at day 5 after obstructive injury. In contrast, the number of bone marrow-derived fibrocytes was significantly reduced in the injured kidney of CXCL16 knockout mice. Fibrocytes expressed CXCR6, the CXCL16 receptor. CXCL16 knockout mice exhibited a significant reduction in CD45, collagen I, and CXCR6 triple positive fibrocytes in response to obstructive injury compared with wild-type mice. Furthermore, targeted deletion of CXCL16 inhibited myofibroblast activation, reduced total collagen deposition, and suppressed expression of collagen I and fibronectin.
Conclusion: CXCL16 plays a pivotal role in the pathogenesis of renal fibrosis by recruiting bone marrow-derived fibrocytes.
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