NDT Advance Access published online on March 25, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn742
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The cyclin kinase inhibitor p57kip2 regulates TGF-β-induced compensatory tubular hypertrophy: effect of the immunomodulator AS101
1 Nephrology Division, Assaf Harofeh Medical Center, Zerifin 2 Safdié Institute for AIDS and Immunology Research, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 3 Department of Internal Medicine C, Assaf Harofeh Medical Center, Zerifin 4 Department of Pathology, Assaf Harofeh Medical Center, Zerifin 5 Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat Gan, Israel
Correspondence and offprint requests to: Inna Sinuani, Nephrology Division, Assaf Harofeh Medical Center, 70300 Zerifin, Israel. Tel: +972-8-977-9383; Fax: +972-8-977-9705; E-mail: sinuanii{at}asaf.health.gov.il
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Abstract |
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Background. Compensatory tubular cell hypertrophy following unilateral nephrectomy is a cell cycle-dependent process. Our previous study showed that treatment of unilaterally nephrectomized rats with the immunomodulator AS101 partially inhibits compensatory hypertrophy of the remaining kidneys through the inhibition of IL-10-induced TGF-β secretion by mesangial cells. The present study is focused on understanding the intracellular mechanism(s) of this phenomenon.
Methods. A total of 120 male Sprague-Dawley rats were unilaterally nephrectomized or sham-operated and treated with AS101 or PBS. Kidney weight and protein/DNA ratio were assessed for each experimental animal. The expression of TGF-β, PCNA, CDK 2, pRb, ppRb, p21Waf1, p27kip1 and p57kip2 proteins in renal tissues was determined by western blot analysis and immunohistochemistry, and the immunoprecipitation of cyclin E complexes was performed.
Results. Compensatory renal growth is initiated by proliferation of resident renal cells that precedes hypertrophy. Changes in TGF-β expression were positively correlated with the amounts of p57kip2, but not with p21Waf1 and p27kip1 expression in the remaining kidneys. Moreover, there was a marked abundance of p57kip2 but not p21Waf1 and p27kip1 binding to the cyclin E complex in PBS-treated unilaterally nephrectomized rats compared to sham-operated animals. Treatment of uninephrectomized rats with AS101 reduced kidney weight and protein/DNA ratio, inhibited TGF-β and p57kip2 expression in the remaining kidneys, and decreased the level of p57kip2 binding to cyclin E complexes.
Conclusion. These results demonstrate that TGF-β-induced compensatory tubular cell hypertrophy is regulated in vivo by p57kip2 but not by the p21Waf1 and p27kip1 cyclin kinase inhibitor proteins.
Keywords: cell cycle; compensatory renal growth; cyclin kinase inhibitor proteins; hypertrophy; transforming growth factor-β
* These authors contributed equally to the work
Received for publication: 11. 5.08
Accepted in revised form: 11.12.08
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