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RAGE‐ and TGF‐ β receptor‐mediated signals converge on STAT5 and p21 waf to control cell‐cycle progression of mesangial cells: a possible role in the development and progression of diabetic nephropathy
Author(s) -
Brizzi Maria Felice,
Dentelli Patrizia,
Rosso Arturo,
Calvi Cristina,
Gambino Roberto,
Cassader Maurizio,
Salvidio Gennaro,
Deferrari Giacomo,
Camussi Giovanni,
Pegoraro Luigi,
Pagano Gianfranco,
Cavallo-Perin Paolo
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-1053fje
Subject(s) - stat5 , cancer research , endocrinology , medicine , transforming growth factor beta , transforming growth factor , mesangial cell , biology , glycation , cell growth , rage (emotion) , signal transduction , microbiology and biotechnology , chemistry , receptor , kidney , neuroscience , biochemistry
The molecular events associated with acute and chronic exposure of mesangial cells (MC) to hyperglycemia were evaluated. We found that, unlike high glucose (HG) and Amadori adducts, advanced glycation end products (AGE) and transforming growth factor‐β (TGF‐β) induced p21 waf expression and accumulation of MC in G 0 /G 1 . TGF‐β1 blockade inhibited AGE‐mediated collagen production but only partially affected AGE‐induced p21 waf expression and cell‐cycle events, indicating that AGE by binding to AGE receptor (RAGE) per se could control MC growth. Moreover, AGE and TGF‐β treatment led to the activation of the signal transduction and activators of transcription (STAT)5 and the formation of a STAT5/p21SIE2 complex. The role of STAT5 in AGE‐ and TGF‐β‐mediated p21 waf expression and growth arrest, but not collagen production, was confirmed by the expression of the dominant negative STAT5 (∆STAT5) or the constitutively activated STAT5 (1*6‐STAT5) constructs. Finally, in p21 waf ‒/‒ fibroblasts both AGE and TGF‐β failed to inhibit cell‐cycle progression. A potential in vivo role of these mechanisms was sustained by the increasing immunoreactivity for the activated STAT5 and p21 waf in kidney biopsies from early to advanced stage of diabetic nephropathy. Our data indicate that AGE‐ and TGF‐β‐mediated signals, by converging on STAT5 activation and p21 waf expression, may regulate MC growth.