Deacetylation of S6 kinase promotes high glucose-induced glomerular mesangial cell hypertrophy and matrix protein accumulation

Falguni Das, Soumya Maity, Nandini Ghosh-Choudhury, Balakuntalam S. Kasinath, Goutam Ghosh Choudhury

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

S6 kinase acts as a driver for renal hypertrophy and matrix accumulation, two key pathologic signatures of diabetic nephropathy. As a post-translational modification, S6 kinase undergoes acetylation at the C terminus. The role of this acetylation to regulate kidney glomerular cell hypertrophy and matrix expansion is not known. In mesangial cells, high glucose decreased the acetylation and enhanced phosphorylation of S6 kinase and its substrates rps6 and eEF2 kinase that lead to dephosphorylation of eEF2. To determine the mechanism of S6 kinase deacetylation, we found that trichostatin A, a pan-histone deacetylase (HDAC) inhibitor, blocked all high glucose-induced effects. Furthermore, high glucose increased the expression and association of HDAC1 with S6 kinase. HDAC1 decreased the acetylation of S6 kinase and mimicked the effects of high glucose, resulting in mesangial cell hypertrophy and expression of fibronectin and collagen I (α2). In contrast, siRNA againstHDAC1inhibited these effects by high glucose.AC-terminal acetylation-mimetic mutant of S6 kinase suppressed high glucose-stimulated phosphorylation of S6 kinase, rps6 and eEF2 kinase, and inhibited the dephosphorylation of eEF2. Also, the acetylation mimetic attenuated the mesangial cell hypertrophyand fibronectin and collagen I (α2) expression. Conversely, an S6 kinase acetylation-deficient mutant induced all the above effects of high glucose. Finally, in the renal glomeruli of diabetic rats, the acetylation of S6 kinase was significantly reduced concomitant with increased HDAC1 and S6 kinase activity. In aggregate, our data uncovered a previously unrecognized role of S6 kinase deacetylation in high glucose-induced mesangial cell hypertrophy and matrix protein expression.

Original languageEnglish (US)
Pages (from-to)9440-9460
Number of pages21
JournalJournal of Biological Chemistry
Volume294
Issue number24
DOIs
StatePublished - Jun 14 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Deacetylation of S6 kinase promotes high glucose-induced glomerular mesangial cell hypertrophy and matrix protein accumulation'. Together they form a unique fingerprint.

Cite this