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mTOR is a key regulator of rental sodium homeostasis

 

Many forms of hypertension are caused by inappropriate activation of epithelial Na+ channel (ENaC), which mediates Na+ reabsorption in the cells of aldosterone-sensitive distal nephron (ASDN). The activation of ENaC is controlled by multiple signaling molecules, including serum/glucocorticoid regulated kinase 1 (SGK1). It has been reported that mTOR regulates SGK1 phosphorylation and activation. Gleason et al. examined the role of mTOR in regulation of ion transport in ASDN, and demonstrated mTOR played a key role in the regulation of Na+ homeostasis, via SGK1-dependent modulation of ENaC activity. The article was published on The Journal of Clinical Investigation.

 

Researchers established mTOR-inactivated WT and Sgk1-/- mice by pharmacological approach. In WT mice, they found PP242 and AZD8055, two competitive inhibitors of mTOR, prevented all mTOR-dependent phosphorylation, and led to natriuresis without influencing K+ homeostasis. In the further experiments using patch clamp, researchers noticed mTOR inhibitors significantly reduced ENaC activity, without altering the activity of K+ inwardly rectifying channels (ROMK channels), on cortical tubule apical membranes. Moreover, Sgk1-/- mice showed compensatory ENaC activity, which dependent on mTOR, but independent on SGK1. Above all, mTOR is a key regulator of Na+ reabsorption by activating of ENaC.

 

Reference:
J Clin Invest. 2014 Nov 21. pii: 73935.10.1172/JCI73935.

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S2218 Torkinib (PP242) Torkinib (PP242) is a selective mTOR inhibitor with IC50 of 8 nM in cell-free assays; targets both mTOR complexes with >10- and 100-fold selectivity for mTOR than PI3Kδ or PI3Kα/β/γ, respectively. Torkinib (PP242) induces mitophagy and apoptosis.
S1555 AZD8055 AZD8055 is a novel ATP-competitive mTOR inhibitor with IC50 of 0.8 nM in MDA-MB-468 cells with excellent selectivity (∼1,000-fold) against PI3K isoforms and ATM/DNA-PK. AZD8055 induces caspase-dependent apoptosis and also induces autophagy. Phase 1.

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