Katahira Shintaro, Barth Mareike, Döpp Robin, Sugimura Yukiharu, Schmidt Vera, Selig Jessica Isabel, Saiki Yoshikatsu, Jankowski Joachim, Marx Nikolaus, Jahnen-Dechent Willi, Lichtenberg Artur, Akhyari Payam
Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany.
Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Front Pharmacol. 2024 Aug 8;15:1412169. doi: 10.3389/fphar.2024.1412169. eCollection 2024.
Chronic kidney disease (CKD) is a risk factor for the development of cardiovascular diseases, e.g., atherosclerosis and calcific aortic valve disease, leading inevitably to valve replacement surgery. CKD patients with bioprosthetic cardiovascular grafts, in turn, have a higher risk of premature graft degeneration. Peroxisome proliferator-activated receptor gamma (PPARγ) activation by pioglitazone has cardio-renal protective properties, and research using a heterotopic valve implantation model has shown anti-degenerative effects of PPARγ activation on bioprosthetic valved grafts (BVG) in rats. The present work aims to analyze a potential protective effect of pioglitazone treatment on BVG in an adenine-induced rat model of CKD.
BVG of Sprague Dawley rats were heterotopically implanted in Wistar rats in an infrarenal position for 4 and 8 weeks. Animals were distributed into three groups for each time point: 1) control group receiving standard chow, 2) CKD group receiving 0.25% adenine and 3) CKD + pioglitazone group (300 mg per kg of 0.25% adenine chow). BVG function was analyzed by echocardiography. Plasma analytes were determined and explanted grafts were analyzed by semi-quantitative real-time PCR, Western blot analysis, histology and immunohistology.PPARγ activation significantly reduced CKD-induced calcification of aortic and valvular segments of BVG by 44% and 53%, respectively. Pioglitazone treatment significantly also reduced CKD-induced intima hyperplasia by 60%. Plasma analysis revealed significantly attenuated potassium and phosphate levels after pioglitazone treatment. Moreover, PPARγ activation led to significantly decreased interleukin-6 gene expression (by 57%) in BVG compared to CKD animals. Pioglitazone treatment leads to functional improvement of BVG.
This study broadens the understanding of the potential value of PPARγ activation in cardio-renal diseases and delineates pioglitazone treatment as a valuable option to prevent bioprosthetic graft failure in CKD. Further mechanistic studies, e.g., using small molecules activating PPARγ signaling pathways, are necessary for the evaluation of involved mechanisms. Additionally, the translation into pre-clinical studies using large animals is intended as the next research project.
慢性肾脏病（CKD）是心血管疾病发生发展的危险因素，如动脉粥样硬化和钙化性主动脉瓣疾病，最终不可避免地导致瓣膜置换手术。而接受生物人工心脏血管移植物的CKD患者，其移植物过早退化的风险更高。吡格列酮激活过氧化物酶体增殖物激活受体γ（PPARγ）具有心脏-肾脏保护特性，并且利用异位瓣膜植入模型的研究已显示PPARγ激活对大鼠生物人工带瓣移植物（BVG）具有抗退化作用。本研究旨在分析吡格列酮治疗对腺嘌呤诱导的CKD大鼠模型中BVG的潜在保护作用。
将Sprague Dawley大鼠的BVG异位植入Wistar大鼠肾下位置4周和8周。每个时间点的动物分为三组：1）接受标准饲料的对照组，2）接受0.25%腺嘌呤的CKD组，3）CKD + 吡格列酮组（每千克含0.25%腺嘌呤饲料中加入300 mg吡格列酮）。通过超声心动图分析BVG功能。测定血浆分析物，并通过半定量实时PCR、蛋白质印迹分析、组织学和免疫组织学分析取出的移植物。PPARγ激活分别使CKD诱导的BVG主动脉段和瓣膜段钙化显著降低44%和53%。吡格列酮治疗还使CKD诱导的内膜增生显著降低60%。血浆分析显示吡格列酮治疗后钾和磷酸盐水平显著降低。此外，与CKD动物相比，PPARγ激活导致BVG中白细胞介素-6基因表达显著降低（降低57%）。吡格列酮治疗可使BVG功能得到改善。
本研究拓宽了对PPARγ激活在心脏-肾脏疾病中潜在价值的认识，并将吡格列酮治疗描述为预防CKD中生物人工移植物失败的有价值选择。进一步的机制研究，如使用激活PPARγ信号通路的小分子，对于评估相关机制是必要的。此外，将其转化为使用大型动物的临床前研究作为下一个研究项目。
