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Research Paper|Volume 13, Issue 6|pp 8026—8039

mTOR inhibition improves mitochondria function/biogenesis and delays cardiovascular aging in kidney transplant recipients with chronic graft dysfunction

Barbara Infante1, Francesco Bellanti2, Michele Correale3, Paola Pontrelli4, Rossana Franzin4, Serena Leo1, Martina Calvaruso1, Silvia Mercuri1, Giuseppe Stefano Netti1, Elena Ranieri5, Natale Daniele Brunetti3, Giuseppe Grandaliano6,7, Loreto Gesualdo4, Gaetano Serviddio2, Giuseppe Castellano1, Giovanni Stallone1
  • 1Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
  • 2C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Italy
  • 3Cardiology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
  • 4Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari, Italy
  • 5Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
  • 6Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
  • 7Università Cattolica del Sacro Cuore, Rome, Italy
Received: November 25, 2020Accepted: March 3, 2021Published: March 23, 2021
https://doi.org/10.18632/aging.202863

Copyright: © 2021 Infante et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

CVD remains the major cause of mortality with graft functioning in Kidney transplant recipients (KTRs), with an estimated risk of CV events about 50-fold higher than in the general population. Many strategies have been considered to reduce the CV risk such as the use of mTOR inhibitors. We evaluate whether chronic mTOR inhibition might influence CV aging in KTRs studying the molecular mechanisms involved in this effect. We retrospectively analyzed 210 KTRs with stable graft function on therapy with CNI and mycophenolic acid (Group A, 105 pts.), or with CNI and mTORi (Everolimus, Group B, 105 pts.). The presence of mTOR inhibitor in immunosuppressive therapy was associated to increase serum levels of Klotho with concomitant reduction in FGF-23, with a significant decrease in left ventricular mass. In addition, KTRs with mTORi improved mitochondrial function/biogenesis in PBMC with more efficient oxidative phosphorylation, antioxidant capacity and glutathione peroxidase activity. Finally, group B KTRs presented reduced levels of inflammaging markers such as reduced serum pentraxin-3 and p21ink expression in PBMC. In conclusion, we demonstrated that mTOR inhibition in immunosuppressive protocols prevents the occurrence and signs of CV aging in KTRs.