Blocking rpS6 phosphorylation exacerbates Tsc1 deletion–induced kidney growth

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

Research output: Contribution to journalArticle

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Abstract

The molecular mechanisms underlying renal growth and renal growth–induced nephron damage remain poorly understood. Here, we report that in murine models, deletion of the tuberous sclerosis complex protein 1 (Tsc1) in renal proximal tubules induced strikingly enlarged kidneys, with minimal cystogenesis and occasional microscopic tumorigenesis. Signaling studies revealed hyperphosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and increased phosphorylation of ribosomal protein S6 (rpS6) in activated renal tubules. Notably, knockin of a nonphosphorylatable rpS6 in these Tsc1-mutant mice exacerbated cystogenesis and caused drastic nephron damage and renal fibrosis, leading to kidney failure and a premature death rate of 67% by 9 weeks of age. In contrast, Tsc1 single-mutant mice were all alive and had far fewer renal cysts at this age. Mechanistic studies revealed persistent activation of mammalian target of rapamycin complex 1 (mTORC1) signaling causing hyperphosphorylation and consequent accumulation of 4E-BP1, along with greater cell proliferation, in the renal tubules of Tsc1 and rpS6 double-mutant mice. Furthermore, pharmacologic treatment of Tsc1 single-mutant mice with rapamycin reduced hyperphosphorylation and accumulation of 4E-BP1 but also inhibited phosphorylation of rpS6. Rapamycin also exacerbated cystic and fibrotic lesions and impaired kidney function in these mice, consequently leading to a premature death rate of 40% within 2 weeks of treatment, despite destroying tumors and decreasing kidney size. These findings indicate that Tsc1 prevents aberrant renal growth and tumorigenesis by inhibiting mTORC1 signaling, whereas phosphorylated rpS6 suppresses cystogenesis and fibrosis in Tsc1-deleted kidneys.

Original languageEnglish (US)
Pages (from-to)1145-1158
Number of pages14
JournalJournal of the American Society of Nephrology
Volume27
Issue number4
DOIs
StatePublished - Jan 1 2016

Fingerprint

Ribosomal Protein S6
Phosphorylation
Kidney
Growth
Carrier Proteins
Premature Mortality
Nephrons
Sirolimus
Carcinogenesis
Fibrosis
tuberous sclerosis complex 1 protein
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Proximal Kidney Tubule
Mortality
Renal Insufficiency
Cysts

ASJC Scopus subject areas

  • Nephrology

Cite this

Blocking rpS6 phosphorylation exacerbates Tsc1 deletion–induced kidney growth. / Wu, Huijuan; Chen, Jianchun; Xu, Jinxian; Dong, Zheng; Meyuhas, Oded; Chen, Jiankang.

In: Journal of the American Society of Nephrology, Vol. 27, No. 4, 01.01.2016, p. 1145-1158.

Research output: Contribution to journalArticle

Wu, Huijuan ; Chen, Jianchun ; Xu, Jinxian ; Dong, Zheng ; Meyuhas, Oded ; Chen, Jiankang. / Blocking rpS6 phosphorylation exacerbates Tsc1 deletion–induced kidney growth. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 4. pp. 1145-1158.
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