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 1

Characterization of PtenptKO mice.

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Characterization of PtenptKO mice. (A–C) Generation of renal proximal tu...
(A–C) Generation of renal proximal tubular cell–specific Pten-KO (PtenptKO) mice. (A) Schematic depicting the generation of PtenptKO mice. Gender-matched Ptenfl/fl littermates were used as controls (PtenCtrl). (B) PCR verification using the primer pairs 5A and P3 (their relative positions are indicated in A and their sequences listed in Methods), with whole-kidney genomic DNA as templates. The 2200-bp band from the WT allele was readily apparent in PtenCtrl mice but only faintly detected in PtenptKO mice. The 280-bp band was detected only in PtenptKO mice but not in control mice. (C) The Cre recombinase gene was detected by PCR as a 410-bp band in PtenptKO mice but not in PtenCtrl mice, with genomic DNA from ear-punch biopsy samples used as templates. (D) Immunofluorescence staining of kidney sections confirmed that the Ggt1-Cre–mediated Pten deletion occurred selectively in the LTA-positive area (blue) but not in the THP- or DBA-positive tubules (red) of PtenptKO mice, while PTEN (green) was ubiquitously expressed in the kidneys of PtenCtrl mice. Scale bars: 100 μm.