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Deacetylation of S6 kinase promotes high glucose–induced glomerular mesangial cell hypertrophy and matrix protein accumulation
- Source :
- J Biol Chem
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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 against HDAC1 inhibited these effects by high glucose. A C-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 hypertrophy and 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.
- Subjects :
- 0301 basic medicine
Glomerular Mesangial Cell
Kidney Glomerulus
Histone Deacetylase 1
mTORC1
EEF2
Biochemistry
Diabetes Mellitus, Experimental
Rats, Sprague-Dawley
03 medical and health sciences
Animals
Humans
Diabetic Nephropathies
Kinase activity
Molecular Biology
030102 biochemistry & molecular biology
Mesangial cell
Kinase
Chemistry
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases
Molecular Bases of Disease
Acetylation
Hypertrophy
Cell Biology
Fibronectins
Rats
Cell biology
Glucose
030104 developmental biology
Sweetening Agents
Mesangial Cells
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 294
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....dae0d101d3541ed94d4267d6b333bcd9
- Full Text :
- https://doi.org/10.1074/jbc.ra118.007023