Phosphorylation of ribosomal protein S6 mediates compensatory renal hypertrophy

Jinxian Xu, Jianchun Chen, Zheng Dong, Oded Meyuhas, Jiankang Chen

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The molecular mechanism underlying renal hypertrophy and progressive nephron damage remains poorly understood. Here we generated congenic ribosomal protein S6 (rpS6) knock-in mice expressing nonphosphorylatable rpS6 and found that uninephrectomy-induced renal hypertrophy was significantly blunted in these knock-in mice. Uninephrectomy-induced increases in cyclin D1 and decreases in cyclin E in the remaining kidney were attenuated in the knock-in mice compared with their wild-type littermates. Uninephrectomy induced rpS6 phosphorylation in the wild-type mice; however, no rpS6 phosphorylation was detected in uninephrectomized or sham-operated knock-in mice. Nonetheless, uninephrectomy stimulated comparable 4E-BP1 phosphorylation in both knock-in and wild-type mice, indicating that mTORC1 was still activated in the knock-in mice. Moreover, the mTORC1 inhibitor rapamycin prevented both rpS6 and 4E-BP1 phosphorylation, significantly blunted uninephrectomy-induced renal hypertrophy in wild-type mice, but did not prevent residual renal hypertrophy despite inhibiting 4E-BP1 phosphorylation in uninephrectomized knock-in mice. Thus, both genetic and pharmacological approaches unequivocally demonstrate that phosphorylated rpS6 is a downstream effector of the mTORC1-S6K1 signaling pathway mediating renal hypertrophy. Hence, rpS6 phosphorylation facilitates the increase in cyclin D1 and decrease in cyclin E1 that underlie the hypertrophic nature of uninephrectomy-induced kidney growth.

Original languageEnglish (US)
Pages (from-to)543-556
Number of pages14
JournalKidney International
Volume87
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • compensatory renal hypertrophy
  • mTORC1-S6K1 signaling
  • rapamycin
  • ribosomal protein rpS6 phosphorylation-deficient knock-in mice
  • uninephrectomy

ASJC Scopus subject areas

  • Nephrology

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