Abstract
Intimal hyperplasia (IH) is a common cause of vasculopathy due to direct endothelial damage (such as post-coronary revascularization) or indirect injury (such as chronic kidney disease, or CKD). Although the attenuation of coronary revascularization-induced IH (direct-vascular-injury-induced IH) by cilostazol, a phosphodiesterase III inhibitor, has been demonstrated, our understanding of the effect on CKD-induced IH (indirect-vascular-injury-induced IH) is limited. Herein, we tested if cilostazol attenuated CKD-induced IH in a mouse model of ischemic-reperfusion injury with unilateral nephrectomy (Chr I/R), a normotensive non-proteinuria CKD model. Cilostazol (50 mg/kg/day) or placebo was orally administered once daily from 1-week post-nephrectomy. At 20 weeks, cilostazol significantly attenuated aortic IH as demonstrated by a 34% reduction in the total intima area with 50% and 47% decreases in the ratios of tunica intima area/tunica media area and tunica intima area/(tunica intima + tunica media area), respectively. The diameters of aorta and renal function were unchanged by cilostazol. Interestingly, cilostazol decreased miR-221, but enhanced miR-143 and miR-145 in either in vitro or aortic tissue, as well as attenuated several pro-inflammatory mediators, including asymmetrical dimethylarginine, high-sensitivity C-reactive protein, vascular endothelial growth factor in aorta and serum pro-inflammatory cytokines (IL-6 and TNF-α). We demonstrated a proof of concept of the effectiveness of cilostazol in attenuating IH in a Chr I/R mouse model, a CKD model with predominantly indirect-vascular-injury-induced IH. These considerations warrant further investigation to develop a new primary prevention strategy for CKD-related IH.
Highlights
Intimal hyperplasia (IH) is a vasculopathy characterized by a differentiation of any cells that form a multilayer compartment at the tunica intima of blood vessels
At 20 weeks, postnephrectomy, Blood urea nitrogen (BUN) and serum creatinine (SCr) progressed to 83±5 and 1.2±0.5 mg/dL in cilostazol-treated mice and 88±6 and 1.2±0.3 mg/dL in placebo-treated mice, respectively (Fig 2C)
Because chronic kidney disease (CKD) increases pro-inflammatory mediators [29, 30] and the association between platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) with miRs in IH pathogenesis has been reported [12, 31, 32], we evaluated the concentration in sera over time to determine the cascade of these mediators in Chr I/R mice
Summary
Intimal hyperplasia (IH) is a vasculopathy characterized by a differentiation of any cells that form a multilayer compartment at the tunica intima of blood vessels. The effects of cilostazol on intimal hyperplasia of chronic kidney disease mouse vascular complications in several chronic disorders including coronary artery disease (CAD), peripheral arterial disease (PAD), and chronic kidney disease (CKD) [1,2,3]. Direct endothelial damage is the most important factor that induced IH in CAD and PAD [3]. Both direct vascular damage (hypertension) and indirect vascular injury (uremia, anemia and chronic inflammatory state) are responsible for IH in CKD [1, 4]. To see if the indirect-vascular-injury-induced IH of CKD exists without hypertension, another CKD model is needed. A CKD model with predominant tubulointerstitial damage, less albuminuria and hypertension is developed by ischemia-reperfusion injury with unilateral nephrectomy (Chr I/R) [5]. We examine indirect-vascularinjury-induced IH in this model
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