Kidney size increases with increasing body mass and in response to the loss of a single kidney but the mechanisms behind these changes are unclear. Recent data reveal context-dependent roles for PTEN-dependent class I PI3K/mTORC2/Akt signalling and PTEN-independent class III PI3K/mTORC1/S6K1 signalling in determining kidney size.
To investigate the role of mTOR signalling in kidney growth, Raymond Harris, Jian-Kang Chen and colleagues selectively deleted Pten—a negative regulator of the class I PI3K/AKT signalling pathway—from proximal tubules of mice. Pten deletion resulted in greatly enlarged kidneys, with activation of the class I PI3K/mTORC2/Akt pathway. Unilateral nephrectomy induced further hypertrophy of the remaining kidney in Pten-knockout mice. “Unilateral nephrectomy did not activate the class I PI3K/mTORC2/AKT pathway, but proximal-tubule-specific Pten-knockout mice exhibited persistent activation of this pathway and kidney hypertrophy, which could be reversed by administration of the mTORC1 inhibitor rapamycin or by proximal-tubule-specific deletion of EGFR,” explains Chen.
Exogenous delivery of amino acids to mimic the increased metabolic requirements after unilateral nephrectomy activated the class III PI3K/mTORC1/S6K1 pathway. “These findings demonstrate context-dependent roles for EGFR-regulated PTEN-dependent class I PI3K/mTORC2/AKT signalling in the adaptation of normal kidney size, and PTEN-independent nutrient-dependent class III PI3K/mTORC1/S6K1 signalling in the compensatory enlargement of the remaining kidney following unilateral nephrectomy,” explains Harris.
References
Chen, J.-K. et al. Phosphatidylinositol 3- kinase signaling determines kidney size. J. Clin. Invest. 10.1172/JCI78945
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Allison, S. Determinants of kidney size. Nat Rev Nephrol 11, 387 (2015). https://doi.org/10.1038/nrneph.2015.86
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DOI: https://doi.org/10.1038/nrneph.2015.86