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Review
. 2016 Jun 21;17(6):975.
doi: 10.3390/ijms17060975.

Role of mTOR Inhibitors in Kidney Disease

Moto Kajiwara  1 , Satohiro Masuda  2
Affiliations
Review

Role of mTOR Inhibitors in Kidney Disease

Moto Kajiwara et al. Int J Mol Sci. .

Abstract

The first compound that inhibited the mammalian target of rapamycin (mTOR), sirolimus (rapamycin) was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui). Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 and TOR2. The mTOR consists of mTOR complex 1 (mTORC1) and mTORC2. Rapalogues including sirolimus, everolimus, and temsirolimus exert their effect mainly on mTORC1, whereas their inhibitory effect on mTORC2 is mild. To obtain compounds with more potent antiproliferative effects, ATP-competitive inhibitors of mTOR targeting both mTORC1 and mTORC2 have been developed and tested in clinical trials as anticancer drugs. Currently, mTOR inhibitors are used as anticancer drugs against several solid tumors, and immunosuppressive agents for transplantation of various organs. This review discusses the role of mTOR inhibitors in renal disease with a particular focus on renal cancer, diabetic nephropathy, and kidney transplantation.

Keywords: diabetic nephropathy; kidney; kidney transplantation; mTOR inhibitor; renal cancer.

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Figures

Figure 1
Figure 1
Chemical structures of mammalian target of rapamycin (mTOR) inhibitors.
Figure 2
Figure 2
Structures of mTORC1 and mTORC2. mTORC1 phosphorylates substrates including S6K, 4E-BP1, and the unc-51-like kinase 1/mammalian autophagy-related gene 13/focal adhesion kinase family-interacting protein of 200 kDa (ULK1/Atg13/FIP200) complex. mTORC2 phosphorylates substrates including serum/glucocorticoid regulated kinase (SGK) 1, Akt, and protein kinase C-α (PKCα).
Figure 3
Figure 3
Interaction of mTOR, rapalogues, and 12-kDa FK506- and rapamycin-binding protein (FKBP12) mTOR contains 2549 amino acids. Rapalogues, mTOR inhibitors, form a complex with FKBP12 that binds to the FKBP-rapamycin binding (FRB) domain [4].
Figure 4
Figure 4
Hypothesized mechanisms of mammalian target of rapamycin (mTOR) inhibitor action in proximal tubular epithelial cells. Rprinted from [35]. Copyright 2012 with permission from Elsevier. (A) during the recovery phase of nephrotoxicant-induced tubular injury, the mTOR pathway in proximal tubular cells is activated to promote cell proliferation; (B) everolimus treatment exerts antiproliferative effects by blocking cell survival pathways. The quantification of urinary LC3 protein could be beneficial in predicting outcomes of treatment with mTOR inhibitors [36].
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