The pharmacological modulation of PPAR- γ as therapeutic strategy in the failure of arteriovenous fistula

The arteriovenous fistula (AVF) is the preferred vascular access for hemodyalisis in patients with chronic kidney disease. However, intimal hyperplasia (IH) and impaired vascular remodelling affect AVF success, resulting in increased morbidity and mortality risks. The peroxisome-proliferator associated receptor (PPAR-γ) is well-known for regulating many pathways associated with cardiovascular disease and IH, such as cell proliferation, migration and inflammatory response. The main aim of this study was to explore the PPAR-γ stimulation in vitro as strategy for mitigating the main IH pathogenic mechanisms. To this goal, the first step was to evaluate the expression of PPAR-γ protein in vascular tissues collected from patients subjected to AVF procedure. Patients were classified into two groups: AVF T0 (normal veins) and AVF T1 (pathological veins with IH). According to immunohistochemistry, we found that PPARγ was less expressed within the stenotic lesion. The next step was to measure the effects of the PPAR-γ agonist, pioglitazone, on cell proliferation and migration. Cell models were: Human Endothelial Umbilical Vein Cells (HUVEC), Human Aortic Smooth Muscle Cells (HAOSMC), and AVF cells (AVFCs), a primary cell model isolated through oragn culture from AVF T0 and AVF T1 tissues. Data obtained from crystal violet stain and MTT assays, elucidated a time and dosedependant decrease of cell growth in HUVEC, HAOSMC, AVF T0 and AVF T1. Scratch wound test highlighted impairment in cell migration too. The anti-proliferative and anti-migratory effects of pioglitazone were reversed by administration of the PPAR-γ inhibitor GW9662, confirming the involvement of PPAR-γ in these pathogenic processes. Further, PPAR-γ induction by pioglitazone took to transcript downregulation of the invasive genes SLUG, MMP-9 and VIMENTIN. Our data support that the pharmacological stimulation of PPAR-γ in vascular cells could reduce IH pathogenesis and prevent AVF failure. This mechanism needs to be deepened to identify novel molecules able to induce PPAR-γ and further intermediate targets for a more effective therapeutic approach.