Phosphatidylinositol 3-kinase signaling determines kidney size
Jian-Kang Chen, … , Eric G. Neilson, Raymond C. Harris
Jian-Kang Chen, … , Eric G. Neilson, Raymond C. Harris
Published May 18, 2015
Citation Information: J Clin Invest. 2015;125(6):2429-2444. https://doi.org/10.1172/JCI78945.
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Research Article Nephrology

Phosphatidylinositol 3-kinase signaling determines kidney size

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.

Authors

Jian-Kang 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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Figure 5

Renal proximal tubule–specific Pten KO increases rpS6 phosphorylation and p21- or p27-positive cells in LTA-positive renal proximal tubules.

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Renal proximal tubule–specific Pten KO increases rpS6 phosphorylation an...
(A) Localization of increased rpS6 phosphorylation in PtenptKO kidneys. Kidney sections were stained with an antibody against S235/236-phosphorylated rpS6 (p-rpS6) and the renal proximal tubule marker LTA. Representative images at ×100 original magnification (left 2 panels) indicating increased p-rpS6 (green) in PtenptKO kidneys (left 2 lower panels) compared with PtenCtrl kidneys (left 2 top panels). Images at ×400 original magnification (third panels, top and bottom rows), along with their respective phase-contrast images (fourth panels, top and bottom rows), confirmed the localization of increased p-rpS6 staining in the cytoplasm of renal proximal tubules (with LTA staining on the brush-border membranes). (B–E) PtenptKO renal proximal tubule cells exhibited increased protein expression of the cell cycle inhibitors p21Cip1/WAF and p27Kip1. Triple immunofluorescence staining revealed significant increases in both p21Cip1/WAF-positive (B and C) and p27Kip1-positive(D and E) cells in the LTA-positive renal proximal tubule cells from PtenptKO mice compared with those from PtenCtrl mice, respectively. Shown are representative images from 5 individual mice per genotype group with similar results. For quantitation of p21Cip1/WAF-positive (C) and p27Kip1-positive (E) cells per 1,000 nuclei in LTA-positive tubules, Mann-Whitney U tests were used for statistical analysis of the data, with the indicated P values from 5 mice per group. Scale bars: 40 μm (left 2 panels of A) and 10 μm (right 2 panels of A, B, and D).