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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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
StatePublished - Jun 1 2015

Fingerprint

Phosphatidylinositol 3-Kinase
Kidney
Phosphatidylinositol 3-Kinases
Hypertrophy
Aminoacylation
Renal Circulation
Sirolimus
Nephrectomy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

Phosphatidylinositol 3-kinase signaling determines kidney size. / Chen, Jiankang; Nagai, Kojiro; Chen, Jianchun; Plieth, David; Hino, Masayo; Xu, Jinxian; Sha, Feng; Ikizler, T. Alp; Quarles, C. Chad; Threadgill, David W.; Neilson, Eric G.; Harris, Raymond C.

In: Journal of Clinical Investigation, Vol. 125, No. 6, 01.06.2015, p. 2429-2444.

Research output: Contribution to journalArticle

Chen, J, Nagai, K, Chen, J, Plieth, D, Hino, M, Xu, J, Sha, F, Ikizler, TA, Quarles, CC, Threadgill, DW, Neilson, EG & Harris, RC 2015, 'Phosphatidylinositol 3-kinase signaling determines kidney size', Journal of Clinical Investigation, vol. 125, no. 6, pp. 2429-2444. https://doi.org/10.1172/JCI78945
Chen, Jiankang ; Nagai, Kojiro ; Chen, Jianchun ; Plieth, David ; Hino, Masayo ; Xu, Jinxian ; Sha, Feng ; Ikizler, T. Alp ; Quarles, C. Chad ; Threadgill, David W. ; Neilson, Eric G. ; Harris, Raymond C. / Phosphatidylinositol 3-kinase signaling determines kidney size. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 6. pp. 2429-2444.
@article{b451fe620a224142974e61c3c1a94d5a,
title = "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.",
author = "Jiankang Chen and Kojiro Nagai and Jianchun Chen and David Plieth and Masayo Hino and Jinxian Xu and Feng Sha and Ikizler, {T. Alp} and Quarles, {C. Chad} and Threadgill, {David W.} and Neilson, {Eric G.} and Harris, {Raymond C.}",
year = "2015",
month = "6",
day = "1",
doi = "10.1172/JCI78945",
language = "English (US)",
volume = "125",
pages = "2429--2444",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

TY - JOUR

T1 - Phosphatidylinositol 3-kinase signaling determines kidney size

AU - Chen, Jiankang

AU - Nagai, Kojiro

AU - Chen, Jianchun

AU - Plieth, David

AU - Hino, Masayo

AU - Xu, Jinxian

AU - Sha, Feng

AU - Ikizler, T. Alp

AU - Quarles, C. Chad

AU - Threadgill, David W.

AU - Neilson, Eric G.

AU - Harris, Raymond C.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84930397700&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930397700&partnerID=8YFLogxK

U2 - 10.1172/JCI78945

DO - 10.1172/JCI78945

M3 - Article

VL - 125

SP - 2429

EP - 2444

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -