MAP Kinase Phosphatase-5 Deficiency Impedes Arteriovenous Fistula Maturation

Arteriovenous fistula (AVF), the gold standard for hemodialysis vascular access, is a vital lifeline for patients with renal failure. However, its low maturation rate remains a significant clinical challenge, incurring high economic costs and delaying treatment initiation. Recent studies have highlighted the broad regulatory role of MAP kinase phosphatase-5 (MKP-5) in various cardiovascular diseases. Nevertheless, its role in AVF maturation is yet to be elucidated. Based on the Gene Expression Omnibus (GEO) datasets and clinical human AVF samples evaluation, venous MKP-5 expression was significantly upregulated in mature AVF compared to failed AVF and normal control vein at both mRNA and protein levels, with no differences observed between failed cases and control veins. Subsequently, the aortocaval fistula model was established in congenic 10-week-old male and female MKP-5 knockout (MKP-5-/-) and wild-type C57Bl/6J (WT) mice. Serial pre- and post-operative ultrasound and histological analyses were performed to evaluate the venous remodeling and AVF maturation phenotypes. The findings demonstrated that MKP-5 deficiency remarkably suppressed venous outward remodeling and inhibited venous hemodynamic adaptation without gender difference. Moreover, loss of MKP-5 markedly decreased AVF lumen area and increased the neointimal-to-lumen area ratio compared to WT mice. Mechanistically, previous reports have shown that high laminar shear suppressed endothelia-to-mesenchymal transition (EndoMT) and vascular smooth muscle cell (VSMC) proliferation compared with oscillatory shear. Our results showed that MKP-5 facilitated high steady shear stress during AVF maturation and protected against excessive EndoMT, VSMC proliferation, and collagen deposition. These effects collectively promoted venous outward remodeling and suppressed neointimal hyperplasia. In conclusion, our study highlights the previously unappreciated critical role of MKP-5 in AVF maturation, offering valuable therapeutic insights for enhancing AVF maturation. This work was partially supported by NIH R01HL153599, an EIA, and a TPA award from the American Heart Association. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.