Abstract
Inflammation plays an important role in the pathogenesis of renal and cardiovascular disease in renovascular hypertension (RVH). Ccl2 is an important mediator of inflammation, and is induced within 24 hours following surgery to establish RVH in the murine 2 kidney 1 clip model, a time prior to onset of interstitial inflammation, fibrosis, or tubular atrophy. We tested the hypothesis that Ccl2 deficiency protects the stenotic kidney (STK) from development of chronic renal damage in mice with renovascular hypertension due to renal artery stenosis (RAS). RAS surgery was performed on wild type (WT) and Ccl2 knock out (KO) mice; animals were studied for four weeks. Renal blood flow was reduced to similar extent in both WT and Ccl2 KO mice with RVH. Perfusion of the stenotic kidney was significantly reduced in Ccl2 KO mice as assessed by magnetic resonance imaging (MRI). Stenotic kidney volume in WT, but not in Ccl2 KO mice, was significantly reduced following surgery. Cortical hypoxia was observed in the stenotic kidney of Ccl2 KO mice, as assessed by blood oxygen level-dependent MRI (BOLD-MRI). Ccl2 KO mice showed less cortical atrophy than WT RAS mice. Ccl2 deficiency reduced the number of infiltrating mononuclear cells and expression of Ccl5, Ccl7, Ccl8, Ccr2 and Cd206. We conclude that Ccl2 is a critical mediator of chronic renal injury in RVH.
Highlights
Recent studies have linked both local and systemic inflammation in the pathogenesis of renal and cardiovascular disease in patients with renovascular hypertension (RVH)[1,2]
Our studies provide further evidence that Ccl[2] plays a key role in mediating renal inflammation in RVH and its deficiency alone can protect against the chronic renal injury
The R2* value, a measure of renal hypoxia, was significantly higher in the stenotic kidney (STK) of knock out (KO) mice which could be due to the fact that perfusion was significantly reduced in KO renal artery stenosis (RAS) mice, whereas perfusion was maintained in wild type (WT) RAS mice, albeit at a reduced cortical volume
Summary
Recent studies have linked both local and systemic inflammation in the pathogenesis of renal and cardiovascular disease in patients with renovascular hypertension (RVH)[1,2]. Immunosuppressive therapy, at least in part, ameliorates renal damage in the angiotensin II infusion model[10] These studies support the notion that therapies to target inflammation may have a role in the management of patients with RVH. A CCR2 selective inhibitor protected the stenotic kidney from development of chronic renal damage in this model[20]. That pharmacological inhibition might have “off-label” effects that may not be due to specific CCR2 inhibition Based on these considerations, we tested the hypothesis that Ccl[2] deficiency alone can protect the stenotic kidney from the development of severe interstitial fibrosis, tubular atrophy, and interstitial inflammation in mice with homozygous deletion of the Ccl[2] gene (Ccl[2] KO mice) subjected to unilateral renal artery stenosis
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