Phosphatidylinositol 3-kinase signaling determines kidney size.

Chen JK, Nagai K, Chen J, Plieth D, Hino M, Xu J, Sha F, Ikizler TA, Quarles CC, Threadgill DW, Neilson EG, Harris RC
J Clin Invest. 2015 125 (6): 2429-44

PMID: 25985273 · PMCID: PMC4497754 · DOI:10.1172/JCI78945

Kidney size adaptively increases as mammals grow and in response to the loss of 1 kidney. It is not clear how kidneys size themselves or if the processes that adapt kidney mass to lean body mass also mediate renal hypertrophy following unilateral nephrectomy (UNX). Here, we demonstrated that mice harboring a proximal tubule-specific deletion of Pten (Pten(ptKO)) have greatly enlarged kidneys as the result of persistent activation of the class I PI3K/mTORC2/AKT pathway and an increase of the antiproliferative signals p21(Cip1/WAF) and p27(Kip1). Administration of rapamycin to Pten(ptKO) mice diminished hypertrophy. Proximal tubule-specific deletion of Egfr in Pten(ptKO) mice also attenuated class I PI3K/mTORC2/AKT signaling and reduced the size of enlarged kidneys. In Pten(ptKO) mice, UNX further increased mTORC1 activation and hypertrophy in the remaining kidney; however, mTORC2-dependent AKT phosphorylation did not increase further in the remaining kidney of Pten(ptKO) mice, nor was it induced in the remaining kidney of WT mice. After UNX, renal blood flow and amino acid delivery to the remaining kidney rose abruptly, followed by increased amino acid content and activation of a class III PI3K/mTORC1/S6K1 pathway. Thus, our findings demonstrate context-dependent roles for EGFR-modulated class I PI3K/mTORC2/AKT signaling in the normal adaptation of kidney size and PTEN-independent, nutrient-dependent class III PI3K/mTORC1/S6K1 signaling in the compensatory enlargement of the remaining kidney following UNX.

MeSH Terms (19)

Animals Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Immunosuppressive Agents Kidney Kidney Diseases Mechanistic Target of Rapamycin Complex 2 Mice Mice, Inbred DBA Mice, Knockout Multiprotein Complexes Organ Size Phosphatidylinositol 3-Kinases Phosphorylation Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases, 90-kDa Signal Transduction Sirolimus TOR Serine-Threonine Kinases

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