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Activation of renal profibrotic TGFβ controlled signaling cascades by calcineurin and mTOR inhibitors
- Source :
- Cellular Signalling. 52:1-11
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
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 these widely used compounds with a specific focus put on mechanisms occurring independent of their respective immunosuppressive action. Herein, the impact of redox modulation, the activation of canonical TGFβ and non-Smad pathways and modulation of autophagy by both classes of immunosuppressive drugs will be highlighted and discussed in a broader perspective. The comprehensive knowledge of profibrotic signaling events specifically accompanying the immunomodulatory activity of these widely used drugs is needed for a reliable benefit-risk assessment under therapeutic regimens.
- Subjects :
- 0301 basic medicine
Calcineurin Inhibitors
Kidney
Tacrolimus
03 medical and health sciences
0302 clinical medicine
Transforming Growth Factor beta
Fibrosis
Animals
Humans
Medicine
Mechanistic target of rapamycin
PI3K/AKT/mTOR pathway
Sirolimus
biology
business.industry
Kinase
Calcineurin
TOR Serine-Threonine Kinases
Autophagy
Cell Biology
medicine.disease
030104 developmental biology
030220 oncology & carcinogenesis
Models, Animal
Cyclosporine
biology.protein
Cancer research
Kidney Diseases
Signal transduction
Reactive Oxygen Species
business
Immunosuppressive Agents
Signal Transduction
Subjects
Details
- ISSN :
- 08986568
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Cellular Signalling
- Accession number :
- edsair.doi.dedup.....4bc83c3d93f123261167fec85d57c677