Open AccessImpact of Cyclin B2 and Cell division cycle 2 on tubular hyperplasia in progressive chronic renal failure rats
Author(s) -
Kumiko Nishihara,
Satohiro Masuda,
Shoichi Nakagawa,
Atsushi Yonezawa,
Takaharu Ichimura,
Joseph V. Bonventre,
Ken Ichi Inui
Publication year - 2010
Publication title -
american journal of physiology. renal physiology./american journal of physiology. renal physiology
Language(s) - English
Resource type - Journals
eISSN - 1931-857X
pISSN - 1522-1466
DOI - 10.1152/ajprenal.00567.2009
Subject(s) - cyclin dependent kinase 1 , cell cycle , hyperplasia , mitosis , cyclin b , cyclin b1 , biology , muscle hypertrophy , medicine , cancer research , endocrinology , cyclin , cyclin a , cyclin d , microbiology and biotechnology , cell , biochemistry
To clarify the specific molecular events of progressive tubular damage in chronic renal failure (CRF), we conducted microarray analyses using isolated proximal tubules from subtotally nephrectomized (Nx) rats as a model of CRF. Our results clearly demonstrated time-dependent changes in gene expression profiles localized to proximal tubules. The expression of mitosis-specific genes Cyclin B2 and Cell division cycle 2 (Cdc2) was significantly and selectively increased in the proximal tubules during the compensated period but decreased to basal level in the end-stage period. Administration of everolimus, a potent inhibitor of mammalian target of rapamycin, markedly reduced compensatory hypertrophy and hyperplasia of epithelial cells, which was accompanied by complete abolishment of the expression of Cyclin B2 and Cdc2 enhancement; renal function was then severely decreased. Treatment with the Cdc2 inhibitor 2-cyanoethyl alsterpaullone clearly decreased epithelial cell hyperplasia, based on staining of phosphorylated histone H3 and Ki-67, while hypertrophy was not inhibited. In conclusion, we have demonstrated roles of Cyclin B2 and Cdc2 in the epithelial hyperplasia in response to Nx. These results advance the knowledge of the contribution of cell cycle regulators, especially M phase, in pathophysiology of tubular restoration and/or degeneration, and these two molecules are suggested to be a marker for the proliferation of proximal tubular cells in CRF.