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Papers In Press, published online ahead of print March 11, 2004
Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, MA 02111
Corresponding Author: jkyriakis{at}tufts-nemc.org
Renal disease is a common complication of diabetes. The initiating events in diabetic nephropathy are triggered by hyperglycemia and, possibly, advanced glycation end products. Subsequently, excess levels of vasoactive peptides (endothelin, ET-1, especially) accumulate in the diabetic kidney; and there is evidence that these peptides mediate many of the pathophysiologic changes associated with diabetic renal disease. These changes include an excess deposition of extracellular matrix into the glomerular basement membrane and renal mesangial cell hypertrophy. Our transcriptional profiling studies have revealed that p8, which encodes a putative basic helix-loop-helix (bHLH) protein, is strongly induced in ET-1-treated renal mesangial cells and in an animal model of diabetic nephropathy. RNA interference (RNAi) experiments indicate that p8 is required for ET-1-induced mesangial cell hypertrophy. Here we show that the p8 polypeptide is a phosphoprotein subject to constitutive degradation by the ubiquitin (Ub) proteasome system. This degradation is mediated by phosphatidyl inositol 3-OH kinase (PI3K) and protein kinase-B/Akt. By contrast, stabilization of the p8 protein requires glycogen synthase kinase-3 (GSK3). Finally, short interfering RNA (siRNA)-mediated RNAi indicates that ET-1-stimulated mesangial cell hypertrophy and p8 mRNA induction require the nuclear factor of activated T cells-4 (NFAT4) transcription factor. Thus, p8 levels in the cell are likely maintained by a balance between signal-dependent transcriptional induction and proteolysis.
J. Biol. Chem, 10.1074/jbc.M312401200
Submitted on November 12, 2003
Revised on March 4, 2004
Accepted on March 11, 2004
The pro-hypertrophic bHLH protein p8 is degraded by the ubiquitin proteasome system in a protein kinase-B/Akt and glycogen synthase kinase-3-dependent manner, while endothelin induction of p8 mRNA and renal mesangial cell hypertrophy require NFAT4
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