Roles of PI3K/AKT/mTOR Axis in Arteriovenous Fistula.

Stefano Ratti,Roberta Fiume,Sara Mongiorgi,Lucio Cocco,Lucia Manzoli,Raffaella Mauro,Giulia Ramazzotti,Cristina Rocchi,Mauro Gargiulo

doi:10.3390/biom12030350

Stefano Ratti, Roberta Fiume + Show 7 more

Open Access

https://doi.org/10.3390/biom12030350

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Abstract

Renal failure is a worldwide disease with a continuously increasing prevalence and involving a rising need for long-term treatment, mainly by haemodialysis. Arteriovenous fistula (AVF) is the favourite type of vascular access for haemodialysis; however, the lasting success of this therapy depends on its maturation, which is directly influenced by many concomitant processes such as vein wall thickening or inflammation. Understanding the molecular mechanisms that drive AVF maturation and failure can highlight new or combinatorial drugs for more personalized therapy. In this review we analysed the relevance of critical enzymes such as PI3K, AKT and mTOR in processes such as wall thickening remodelling, immune system activation and inflammation reduction. We focused on these enzymes due to their involvement in the modulation of numerous cellular activities such as proliferation, differentiation and motility, and their impairment is related to many diseases such as cancer, metabolic syndrome and neurodegenerative disorders. In addition, these enzymes are highly druggable targets, with several inhibitors already being used in patient treatment for cancer and with encouraging results for AVF. Finally, we delineate how these enzymes may be targeted to control specific aspects of AVF in an effort to propose a more specialized therapy with fewer side effects.

Highlights

HD requires adequate vascular access, for instance through an arteriovenous fistula, a graft or a tunnelled catheter: these manipulations have a strong impact on patient quality of life, life expectancy, morbidity and mortality [1–3,7]
In this review we focused on the potential roles that phosphoinositides (PPIns) can have in modulating important aspects of Arteriovenous fistula (AVF), such as cell proliferation, vein wall thickening or inflammation, that could influence new or additional therapies valuable for a more personalized AVFpositive patient life
In this review we focus on PI3K/AKT/mTOR signalling as the key phosphoinositide players to illustrate their potential value for AV fistulas

Summary

Arteriovenous Fistula

Renal failure is a real increasing public health issue. Over 75 million people worldwide suffer from chronic kidney disease (CKD), more than patients with diabetes, osteoarthritis or depression. Efferent vein wall remodelling can be abnormal and can lead to AVF vein myointimal thickening and/or aneurysmatic fistula degeneration and to AVF failure (Figure 2): this process is usually associated with KI67 expression, a known marker of cell proliferation [12]. Even if present-day treatments are improving patient conditions, AVF has a high rate 3 of review of early or late failure; new or additional treatments are necessary In this we focused on the potential roles that phosphoinositides (PPIns) can have in modulating important aspects of AVF, such as cell proliferation, vein wall thickening or inflammation, obtained human vascular cells,valuable. In this review we focused on the potential roles that phosphoinositides (PPIns) can have in modulating important aspects of AVF, such as cell proliferation, vein wall thickening or inflammation, that could influence new or additional therapies valuable for a more personalized AVFpositive patient life. Achieved that persists during 36 months from AVF creation without important variations [12]

Phosphoinositides

Findings

Conclusions