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Cilostazol attenuates intimal hyperplasia in a mouse model of chronic kidney disease
Wiwat Chancharoenthana1,2, Asada Leelahavanichkul3,4, Sujittra Taratummarat3
1Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
Insights
Cilostazol, a phosphodiesterase III inhibitor, effectively reduces intimal hyperplasia (IH) in a mouse model of chronic kidney disease (CKD). This study demonstrates cilostazol
Area of Science:
- Vascular Biology and Medicine
- Nephrology and Urology
- Pharmacology
Background:
- Intimal hyperplasia (IH) is a significant cause of vasculopathy, often resulting from direct endothelial damage or indirect injury like chronic kidney disease (CKD).
- While cilostazol's efficacy against direct vascular injury-induced IH is known, its impact on CKD-induced IH remains less understood.
- CKD-associated vasculopathy presents a major clinical challenge, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the potential of cilostazol in attenuating IH in a mouse model of CKD characterized by indirect vascular injury.
- To evaluate the molecular mechanisms underlying cilostazol's effects on CKD-induced IH.
Main Methods:
- A mouse model of chronic ischemic-reperfusion injury with unilateral nephrectomy (Chr I/R) was utilized to simulate CKD.
- Cilostazol (50 mg/kg/day) or placebo was administered orally for 19 weeks post-nephrectomy.
- Vascular morphometry, renal function tests, and molecular analyses (miRNA expression, inflammatory markers) were performed.
Main Results:
- Cilostazol significantly reduced aortic intimal hyperplasia by 34% in the Chr I/R model.
- The treatment decreased the ratios of tunica intima area to tunica media area and intima area to total vessel area.
- Cilostazol modulated specific microRNAs (decreased miR-221, increased miR-143/145) and attenuated key inflammatory mediators.
Conclusions:
- Cilostazol demonstrates a proof-of-concept efficacy in attenuating indirect vascular injury-induced IH in a preclinical CKD model.
- These findings suggest cilostazol as a potential therapeutic agent for preventing CKD-related vasculopathy.
- Further research is warranted to explore cilostazol for primary prevention strategies in CKD patients.
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.
