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Pioglitazone treatment mitigates cardiovascular bioprosthetic degeneration in a chronic kidney disease model
Shintaro Katahira1,2, Mareike Barth1,3, Robin Döpp1
1Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany.
Insights
Pioglitazone treatment protects bioprosthetic valved grafts (BVG) from degeneration in chronic kidney disease (CKD) rats. This PPARγ activation reduces calcification and improves BVG function, offering a potential therapy for cardiovascular graft failure in CKD patients.
Area of Science:
- Cardiovascular Medicine
- Nephrology
- Biomaterials Science
Background:
- Chronic kidney disease (CKD) increases cardiovascular disease risk, including atherosclerosis and calcific aortic valve disease, often necessitating valve replacement.
- Bioprosthetic cardiovascular grafts (BVG) in CKD patients face accelerated degeneration, leading to premature graft failure.
- Peroxisome proliferator-activated receptor gamma (PPARγ) activation, notably by pioglitazone, exhibits cardio-renal protective effects.
Purpose of the Study:
- To investigate the protective effects of pioglitazone treatment on bioprosthetic valved grafts (BVG) in a rat model of chronic kidney disease (CKD).
- To evaluate whether PPARγ activation can mitigate CKD-induced degeneration of cardiovascular grafts.
Main Methods:
- Bioprosthetic valved grafts (BVG) were implanted in rats, with animals subjected to adenine-induced chronic kidney disease (CKD) and treated with either placebo or pioglitazone.
- Graft function was assessed via echocardiography, with plasma analytes measured and explanted grafts analyzed using molecular and histological techniques.
- Key endpoints included graft calcification, intimal hyperplasia, inflammatory markers (interleukin-6), and overall graft function.
Main Results:
- PPARγ activation by pioglitazone significantly reduced CKD-induced calcification in both aortic (44%) and valvular (53%) segments of BVG.
- Pioglitazone treatment markedly decreased intimal hyperplasia (60%) and attenuated elevated potassium and phosphate levels in CKD rats.
- Interleukin-6 gene expression in BVG was significantly reduced (57%) with pioglitazone, indicating reduced inflammation and improved graft function.
Conclusions:
- Pioglitazone treatment, through PPARγ activation, demonstrates significant protective effects against bioprosthetic graft degeneration in a CKD setting.
- This study highlights pioglitazone as a promising therapeutic strategy to prevent bioprosthetic graft failure in patients with chronic kidney disease.
- Further research into the mechanistic pathways and translation to pre-clinical large animal models is warranted.
Aims:
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.
Methods And Results:
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.
Conclusion:
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.
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