Abstract: TH-PO371
Angiotensin II Selectively Activates SGK1, but Not Akt, via PKC-Dependent Modulation of mTORC2 in Renal Tubule Epithelial Cells
Session Information
- Cell Signaling and Oxidative Stress
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Cell Biology
- 201 Cell Signaling, Oxidative Stress
Authors
- Gleason, Catherine, University of California San Francisco, San Francisco, California, United States
- Pearce, David, University of California San Francisco, San Francisco, California, United States
Background
Angiotensin II (AngII) is a potent regulator of fluid balance and blood pressure homeostasis. In volume depletion, AngII stimulates production of the sodium retaining hormone, aldosterone, but also directly effects salt reabsorption through regulation of ion transporters located in various segments of the kidney tubules. Elevated circulating and local tissue AngII levels are a significant factor in the development of sodium and fluid retention and hypertension. Serum- and glucocorticoid-regulated kinase 1(SGK1) is implicated as a mediator of Ang II action, however, the molecular mechanisms underlying activation of SGK1 by AngII are not completely understood. SGK1 plays an important role in regulation of sodium and potassium transport in renal tubules of the kidney through activation of ENaC and NCC (in the cortical collecting duct (CCD) and distal connecting tubule (DCT), respectively), and NHE3 (in the proximal tubule (PT)).
Results
SGK1 and the highly related kinase, Akt, are activated by mTOR through phosphorylation of a critical, homologous residue within their hydrophobic motif (HM). mTOR, an atypical serine/threonine kinase, is the catalytic core of two functionally distinct multi-protein complexes, mTORC1 and mTORC2. mTORC1 consists of mLST8, DEPTOR, PRAS40, and RAPTOR. mTORC2, also contains mLST8 and DEPTOR, but is defined by the presence of RICTOR, SIN1 and PROTOR. We find that AngII triggers selective mTORC2-dependent activation of SGK1 but not Akt. PKC activity is required for the AngII-stimulated SGK1 S422 phosphorylation and is mediated in part by PKC-induced SIN1 phosphorylation at three serine residues: S128, S315 and S356.
Conclusion
Our findings provide a mechanism for selective regulation of the mTORC2 substrate, SGK1, which is dependent on cPKC. Considering the well-described roles of SGK1 and Akt in regulation of ion and glucose homeostasis, respectively, these findings have important implications for defining molecular mechanisms that specify selective control of ion balance and glucose metabolism. Our results are particularly compelling in the context of metabolic diseases such as diabetes and obesity, which are frequently associated with impaired ion balance and hypertension.
Funding
- NIDDK Support