Activation of renal profibrotic TGFβ controlled signaling cascades by calcineurin and mTOR inhibitors

Cellular Signalling
Wolfgang EberhardtJosef Pfeilschifter

Abstract

The calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus represent potent immunosuppressive agents frequently used for solid organ transplantation and treatment of autoimmune disorders. Despite of their immense therapeutic benefits, residual fibrosis mainly in the kidney represents a common side effect of long-term therapy with CNI. Regardless of the immunosuppressive action, an increasing body of evidence implicates that a drug-induced increase in TGFβ and subsequent activation of TGFβ-initiated signaling pathways is closely associated with the development and progression of CNI-induced nephropathy. Mechanistically, an increase in reactive oxygen species (ROS) generation due to drug-induced changes in the intracellular redox homeostasis functions as an important trigger of the profibrotic signaling cascades activated under therapy with CNI. Although, inhibitors of the mechanistic target of rapamycin (mTOR) kinase have firmly been established as alternative compounds with a lower nephrotoxic potential, an activation of fibrogenic signaling cascades has been reported for these drugs as well. This review will comprehensively summarize recent advances in the understanding of profibrotic signaling events modulated by th...Continue Reading

Citations

Dec 19, 2018·Journal of Clinical Medicine·Claudio Ponticelli, Gabriella Moroni
Dec 24, 2019·Expert Opinion on Investigational Drugs·Daren R UreRobert T Foster
Feb 11, 2020·Journal of Biochemical and Molecular Toxicology·Yi LuJin-Jun Liu
Jun 20, 2021·Transplant International : Official Journal of the European Society for Organ Transplantation·Rachel HellemansUNKNOWN for ESOT Workstream 3 of the TLJ (Transplant Learning Journey) project

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