RAGE‐ and TGF‐ β receptor‐mediated signals converge on STAT5 and p21^wafto control cell‐cycle progression of mesangial cells: a possible role in the development and progression of diabetic nephropathy

Abstract

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-beta (TGF-beta) induced p21waf expression and accumulation of MC in G0/G1. TGF-beta1 blockade inhibited AGE-mediated collagen production but only partially affected AGE-induced p21waf expression and cell-cycle events, indicating that AGE by binding to AGE receptor (RAGE) per se could control MC growth. Moreover, AGE and TGF-beta 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-beta-mediated p21waf expression and growth arrest, but not collagen production, was confirmed by the expression of the dominant negative STAT5 (DeltaSTAT5) or the constitutively activated STAT5 (1*6-STAT5) constructs. Finally, in p21waf-/- fibroblasts both AGE and TGF-beta 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-beta-mediated signals, by converging on STAT5 activation and p21waf expression, may regulate MC growth.

Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and β4 Integrin Expression

“…In Table 1 we show that following 48 or 72 h of stimulation with ox-LDL, the proportion of cells in the S phase was increased. Conversely, as reported previously (33), AGE failed to induce cell cycle progression. A dose-response curve (from 10 to 100 g/ml ox-LDL) indicated that ox-LDL concentrations above 60 g/ml led to apoptosis.…”

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

“…Muscle sections were processed for immunofluorescence assays and immunohistochemistry analyses as previously described (29). A quantification of cells that expressed the indicated markers was obtained as previously described (30). Images were acquired using a Zeiss LSM 5 Pascal confocal laser-scanning microscope (Carl Zeiss, Jena, Germany) (19).…”

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

“…20 The mechanism is unknown and may involve receptors that can be activated by anionic ligands. 10,21 Thus, we propose that increased negative charge because of increased CML content in glycated collagen IV results in inhibition of mesangial cell proliferation. Blocking CML formation using PM diminished the negative charge of glycated collagen and protected cell proliferation.…”

“…9 Circulating AGE-albumin also causes mesangial cell damage by affecting cell growth and collagen expression. 10 However, the cellular effects of ECM modifications may be different from the direct cellular toxicity of glucose, reactive carbonyl species, or circulating glycated albumin. Moreover, because these modifications accumulate on long-lived ECM proteins such as collagen IV, their effects would continue long after the levels of glucose and other cir-culating pathogenic factors are normalized.…”