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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
January 2012 Issue of IMpact