Effects of PPAR-Gamma Activation on In Vivo Degeneration of Allografts in a Model of Chronic Kidney Disease

Objectives: Patients with renal failure have problems with calcification of the cardiovascular system and require invasive procedures such as valve replacement. Bioprosthetic valves do not require anticoagulant therapy, but functional deterioration due to calcification over time remains a problem. Pioglitazone as a PPAR-gamma agonist is known to have not only an anti-diabetic effect but also anti-inflammatory and anti-arteriosclerotic action on the cardiovascular system. In this study, we aimed to examine the anti-inflammatory and anti-calcification effects of pioglitazone on bioprosthetic aortic valve grafts in a small animal model of chronic kidney disease (CKD).

Methods: A total of 60 Wister rats were divided randomly into three groups. Rats fed only the normal diet were designated as control group (C group) [SY-U1]. Rats were fed with 0.25% adenine to induce chronic renal failure model (CKD group). Half of CKD animals received pioglitazone (CKD+P group). Cryopreserved aortic grafts including the aortic valve from donor rats were transplanted into the abdominal aorta. Ten animals of each group were sacrificed and the grafts were collected for pathological and RT-PCR analysis after 4 and 8 weeks, respectively.

Result: Rats receiving 0.25% adenine showed a significant increase of creatinine levels at 4 and 8 weeks as compared with the C group [SY-U1] [APPD2]. After 8 weeks, intimal proliferation [SY-U3] [APPD4] occurred in CKD, which was significantly suppressed by pioglitazone in CKD+P (p = 0.004). Moreover, CKD+P aortic grafts showed significantly less media calcification (p = 0.037 and p = 0.022 for comparison at 4 and 8 weeks, respectively). Upon PCR, phosphate transporter-1 (PiT-1) and IL-6 elevation were observed, which was favorably lower in CKD+P than in CKD at 4 weeks.

Conclusion: Pioglitazone inhibits graft degeneration [SY-U1] [APPD2] of bioprostheses in a small animal model of CKD. Further studies are needed to elucidate a possible anti-inflammatory effect as suggested here by reduced PiT-1 and IL-6 levels.

Publication History

Article published online:
19 February 2021