Estradiol reverses TGF-βinduced mesangial cell apoptosis by a casein kinase 2-dependent mechanism

Olivia Negulescu, Istvan Bognar, Jun Lei, Prasad Devarajan, Sharon Silbiger, Joel Neugarten

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Background. The slower rate of progression of chronic renal disease in women than in men is explained in part by the ability of estradiol to reverse the stimulatory effect of transforming growth factor-β (TGF-β1) on collagen IV synthesis at the level of casein kinase 2 activation. Casein kinase 2 also phosphorylates and activates the pro-apoptotic protein, p53. We hypothesized that estradiol would reverse TGF-β1-induced mesangial cell apoptosis by antagonizing the stimulatory effects of TGF-β1 on casein kinase 2 activity, thereby preventing p53 activation. Methods. The effects of TGF-β1 on mesangial cell apoptosis, p53 phosphorylation, Bax and Bcl-2 levels, caspase 9 activity, and cleavage of PARP were examined. The abilities of estradiol and a specific inhibitor of CK2 (5,6-dichloro-1-β-D-ribofurano-sylbenzimidazole) (DRB) to modulate the effects of TGF-β1 on these processes were also examined. Results. TGF-β1 (2 ng/mL), which up-regulates CK2 activity, induces apoptosis in murine mesangial cells together with p53 serine389 phosphorylation, up-regulation of Bax, suppression of Bcl-2, destabilization of mitochondrial permeability transition pores, stimulation of caspase 9 activity and activation of PARP. TGF-β1-induced p53 activation and all the intermediary steps leading to mesangial cell apoptosis were reversed by estradiol (10-9 mol/L) and by DRB, potent inhibitors of CK2 activity, but not by inhibitors of the p38 MAPK, ERK or JNK signaling cascades. In contrast, TGF-β1 failed to induce apoptosis in p53 knockout mesangial cells. Conclusions. Our data suggest that CK2 mediates the stimulatory effects of TGF-β1 on mesangial cell apoptosis via a p53-dependent mechanism. The ability of estradiol to reverse TGF-β1-induced apoptosis may contribute to the protective effects of female gender on the course of chronic renal disease.

Original languageEnglish (US)
Pages (from-to)1989-1998
Number of pages10
JournalKidney international
Volume62
Issue number6
DOIs
StatePublished - Dec 2002

Keywords

  • Apoptosis
  • Chronic renal failure
  • Gender and renal disease
  • Progressive renal disease
  • Sex hormones
  • Transforming growth factor-β
  • Type IV collagen protein synthesis

ASJC Scopus subject areas

  • Nephrology

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