Estradiol reverses TGF-β1-induced 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

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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 - 2002

Fingerprint

Casein Kinase II
Mesangial Cells
Estradiol
Apoptosis
Dichlororibofuranosylbenzimidazole
Caspase 9
Chronic Renal Insufficiency
Up-Regulation
Phosphorylation
Apoptosis Regulatory Proteins
Transforming Growth Factors
p38 Mitogen-Activated Protein Kinases
Collagen

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

Cite this

Estradiol reverses TGF-β1-induced mesangial cell apoptosis by a casein kinase 2-dependent mechanism. / Negulescu, Olivia; Bognar, Istvan; Lei, Jun; Devarajan, Prasad; Silbiger, Sharon; Neugarten, Joel.

In: Kidney International, Vol. 62, No. 6, 2002, p. 1989-1998.

Research output: Contribution to journalArticle

Negulescu, Olivia ; Bognar, Istvan ; Lei, Jun ; Devarajan, Prasad ; Silbiger, Sharon ; Neugarten, Joel. / Estradiol reverses TGF-β1-induced mesangial cell apoptosis by a casein kinase 2-dependent mechanism. In: Kidney International. 2002 ; Vol. 62, No. 6. pp. 1989-1998.
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T1 - Estradiol reverses TGF-β1-induced mesangial cell apoptosis by a casein kinase 2-dependent mechanism

AU - Negulescu, Olivia

AU - Bognar, Istvan

AU - Lei, Jun

AU - Devarajan, Prasad

AU - Silbiger, Sharon

AU - Neugarten, Joel

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

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KW - Gender and renal disease

KW - Progressive renal disease

KW - Sex hormones

KW - Transforming growth factor-β

KW - Type IV collagen protein synthesis

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