The Ups and Downs of TORKinibs in Transplantation
Abstract
Use of the immunosuppressive mechanistic target of rapamycin (mTOR) inhibitor Rapamycin (RAPA) in renal transplantation has diminished due to more intolerable side effects and higher rejection rates compared to calcineurin inhibitors. By binding the immunophilin FKBP12, RAPA inhibits mTOR complex 1 (mTORC1), while prolonged exposure is required to inhibit assembly of mTORC2. Paradoxically, brief exposure to RAPA can activate the mTORC2- protein kinase B (AKT) pathway through inhibition of negative feedback loops mediated by mTORC1. While mTORC1 responds to environmental cues to regulate cell growth and anabolism, mTORC2 promotes cell survival and regulates the actin cytoskeleton. TORKinibs differ from RAPA and related compounds (Rapalogs) in that they work through an adenosine triphosphate (ATP)-competitive mechanism and block the catalytic function of both mTORC1 and mTORC2.
Recent publications fuel debate as to whether targeted mTORC1 and mTORC2 inhibition could emerge as an alternative therapy in transplantation. Ischemia-reperfusion injury (IRI) causes delayed graft function and impairs graft survival. Of direct relevance to IRI is autophagy, a catabolic process of cell preservation via which large substrates, including proteins, organelles and invading microorganisms, are captured and sequestered for lysosomal degradation. Recent studies suggest that in renal IRI, autophagy (in tubular cells) is an early event that precedes apoptosis and is renoprotective. While mTORC1…
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