Phosphatidylinositol 3-kinase signaling determines kidney size

Jiankang Chen, Kojiro Nagai, Jianchun Chen, David Plieth, Masayo Hino, Jinxian Xu, Feng Sha, T. Alp Ikizler, C. Chad Quarles, David W. Threadgill, Eric G. Neilson, Raymond C. Harris

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19 Scopus citations

Abstract

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 (PtenptKO) 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 p21Cip1/WAF and p27Kip1. Administration of rapamycin to PtenptKO mice diminished hypertrophy. Proximal tubule-specific deletion of Egfr in PtenptKO mice also attenuated class I PI3K/mTORC2/AKT signaling and reduced the size of enlarged kidneys. In PtenptKO 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 PtenptKO 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.

Original languageEnglish (US)
Pages (from-to)2429-2444
Number of pages16
JournalJournal of Clinical Investigation
Volume125
Issue number6
DOIs
Publication statusPublished - Jun 1 2015

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ASJC Scopus subject areas

  • Medicine(all)

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Chen, J., Nagai, K., Chen, J., Plieth, D., Hino, M., Xu, J., ... Harris, R. C. (2015). Phosphatidylinositol 3-kinase signaling determines kidney size. Journal of Clinical Investigation, 125(6), 2429-2444. https://doi.org/10.1172/JCI78945