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Blockade of CCR2 reduces macrophage influx and development of chronic renal
damage in murine renovascular hypertension
#MMPMID26661648
Kashyap S
; Warner GM
; Hartono SP
; Boyilla R
; Knudsen BE
; Zubair AS
; Lien K
; Nath KA
; Textor SC
; Lerman LO
; Grande JP
Am J Physiol Renal Physiol
2016[Mar]; 310
(5
): F372-84
PMID26661648
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Renovascular hypertension (RVH) is a common cause of both cardiovascular and
renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the
stenotic kidney is associated with an influx of macrophages and other mononuclear
cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would
reduce chronic renal injury by reducing macrophage influx in the stenotic kidney
of mice with RAS. We employed a well-established murine model of RVH to define
the relationship between macrophage infiltration and development of renal atrophy
in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2
signaling in the development of renal atrophy, mice were treated with the CCR2
inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal
tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at
which no significant light microscopic alterations, including interstitial
inflammation, were identified. Macrophage influx increased with time following
surgery. At 4 wk, the development of severe renal atrophy was accompanied by an
influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that
coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1
and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and
significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+
but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+
macrophage accumulation that coexpress F4/80 and renal atrophy in experimental
renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to
humans with RVH.
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