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 13

UNX induces increased RBF and renal delivery of amino acids, activates class III PI3K, and induces mTOR localization on the lysosomal membrane in the remaining kidney.

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UNX induces increased RBF and renal delivery of amino acids, activates c...
(A) An immediate increase in RBF in mice occurred upon ligation of the contralateral renal pedicle, followed by gradually decreased RBF initiated by an overdose perfusion of isoflurane. RBF is expressed as blood perfusion units (BPU). (B) Significant increases were observed in free amino acid content in the remaining kidney of mice in response to UNX (U) compared with sham-operated mice (S). ANOVA with Bonferroni’s t correction was used for statistical analysis of the data. *P < 0.001 indicates a comparison between group U versus group S at each time point, respectively. No significant difference was seen in the S group at different time points (P > 0.05). n = 5 mice per group per time point. (C) Class III PI3K kinase activity in the left kidney was measured using the same lipid kinase activity assay as in Figure 11A after 8-week-old male DBA/2 mice were subjected to right sham or UNX surgery for the indicated time periods, with the lower panel showing immunoprecipitated class III PI3K. (D) Eight-week-old male DBA/2 mice were subjected to right sham or UNX surgery. The mice were sacrificed 6 hours later to harvest and process the left kidney for immunofluorescence staining and confocal microscopy to detect the localization of mTOR and LAMP1. n = 5 mice per treatment group for animal experiments with similar results. Scale bar: 5 μm.