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Abstract: FR-PO393

Deacetylation of S6 Kinase (S6K) by High Glucose Drives Mesangial Cell (MC) Hypertrophy and Matrix Expansion in Diabetic Nephropathy (DN)

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Das, Falguni, UTHSCSA, SAN ANTONIO, Texas, United States
  • Ghosh-choudhury, Nandini, UTHSCSA, SAN ANTONIO, Texas, United States
  • Kasinath, Balakuntalam S., UTHSCSA, SAN ANTONIO, Texas, United States
  • Ghosh-Choudhury, Goutam, UTHSCSA, SAN ANTONIO, Texas, United States

Hyperglycemia increases mTORC1-dependent S6K Thr-389 phosphorylation/activation to induce glomerular MC hypertrophy and matrix protein expansion in DN. S6K is acetylated in the C-terminal lysines (K484/485/493). We investigated the mechanism of S6K acetylation in relation to MC hypertrophy and fibronectin expression.


Human MCs in culture and streptozotocin (STZ)-induced diabetic rats were used. Activation/inactivation-specific phospho-antibodies, siRNA and plasmid-derived expression vector transfection and immunoblotting were employed.


In MCs, 25 mM glucose (HG) decreased acetylation of multiple proteins including S6K concomitant with its increase in phosphorylation/activation. Consequently, HG increased phosphorylation of the S6K substrates rps6 and eEF2 kinase that resulted in dephosphorylation of eEF2. To determine the mechanism of S6K deacetylation, we considered the class I histone deacetylase-1 (HDAC1). Trichostatin-A (TSA), a pan HDAC inhibitor, blocked all of the HG-stimulated effects. HG increased the association of S6K with HDAC1. Expression of HDAC1 decreased the acetylation of S6K and increased the phosphorylation of S6K, rps6, eEF2 kinase, and dephosphorylation of eEF2, resulting in MC hypertrophy and expression of fibronectin, similar to HG. In contrast, siRNA against HDAC1 prevented these effects induced by HG. To study the precise mechanism, an acetylation mimetic triple mutant (TKA) was used. Expression of TKA blocked HG-stimulated phosphorylation of S6K, rps6, eEF2 kinase and inhibited the dephosphorylation of eEF2 resulting in attenuation of MC hypertrophy and fibronectin expression. In contrast, acetylation deficient mutant S6K (TKR) induced above phosphorylation events, and MC hypertrophy and fibronectin expression, similar to HG. Finally, in the renal glomeruli of STZ-induced diabetic rats, acetylation of S6K was significantly reduced concomitant with increased HDAC1, S6K activation, phosphorylation of rps6 and eEF2 kinase, dephosphorylation of eEF2, renal hypertrophy and fibronectin expression.


Our data for the first time show a role of S6K deacetylation in MC hypertrophy and matrix expansion, two pathologic features of DN. The results also furnish a molecular basis underlying the association between S6K and HDAC1 in DN.


  • Veterans Affairs Support