Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges

Abstract

The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has a key role in the regulation of a variety of biological processes pivotal for cellular life, aging, and death. Impaired activity of mTOR complexes (mTORC1/mTORC2), particularly mTORC1 overactivation, has been implicated in a plethora of age-related disorders, including human renal diseases. Since the discovery of rapamycin (or sirolimus), more than four decades ago, advances in our understanding of how mTOR participates in renal physiological and pathological mechanisms have grown exponentially, due to both preclinical studies in animal models with genetic modification of some mTOR components as well as due to evidence coming from the clinical experience. The main clinical indication of rapamycin is as immunosuppressive therapy for the prevention of allograft rejection, namely, in renal transplantation. However, considering the central participation of mTOR in the pathogenesis of other renal disorders, the use of rapamycin and its analogs meanwhile developed (rapalogues) everolimus and temsirolimus has been viewed as a promising pharmacological strategy. This article critically reviews the use of mTOR inhibitors in renal diseases. Firstly, we briefly overview the mTOR components and signaling as well as the pharmacological armamentarium targeting the mTOR pathway currently available or in the research and development stages. Thereafter, we revisit the mTOR pathway in renal physiology to conclude with the advances, drawbacks, and challenges regarding the use of mTOR inhibitors, in a translational perspective, in four classes of renal diseases: kidney transplantation, polycystic kidney diseases, renal carcinomas, and diabetic nephropathy.

MTOR promotes basal cell carcinoma growth through atypical PKC

“…To explore whether mTor inhibition can be used as an effective BCC therapeutic, we grew BCC tumors in Ptch1 fl/fl ; Gli1-Cre ERT2 mice for 5 weeks after tamoxifen injection and intraperitoneally injected either DMSO or 3 mg/kg everolimus once a day for seven days. We used everolimus despite a slight increase in Gli1 expression in ASZ001 mouse BCC cells because it is FDA approved and has been shown to be more effective in treating certain cancers and other diseases than rapamycin [29,30,31,32] . Histological staining of the dorsal skin of everolimus-treated mice showed a significant reduction in total tumor area compared to DMSO controls (Figure 4A-B).…”

MiR‐183 delivery attenuates murine lupus nephritis‐related injuries via targeting mTOR

“…Rapamycin, a potent immunosuppressive agent and mTOR inhibitor, has been demonstrated to have strong activity in inhibition of allograft rejection in animal models of transplantation . Rapamycin was shown to be a potent inhibitor of S6K1 kinase activation and an important mediator of PI3 kinase signalling.…”

mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

“…Inhibition of mTOR by rapamycin or one of its analogues represents a potentially novel treatment for autosomal dominant polycystic kidney disease. mTOR modulators for renal recovery are already ongoing clinical trials and were reviewed in 2018 [79].…”

“…Mouse [58,59,61], Human [69] Kidney mTORC1 mediates hypertrophic response following kidney injuries. Rat [75,79] Whole-body mTOR genes are downregulated during pre-regenerative autophagy but activity is required for initial mitotic response and blastema formation.…”