Impact of Cyclin B2 and Cell division cycle 2 on tubular hyperplasia in progressive chronic renal failure rats.
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.
Nishihara
Kumiko
K
Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
Masuda
Satohiro
S
Nakagawa
Shunsaku
S
Yonezawa
Atsushi
A
Ichimura
Takaharu
T
Bonventre
Joseph V
JV
Inui
Ken-ichi
K
D000818:Animals; D016203:CDC2 Protein Kinase; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D056765:Cyclin B2 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases; D000068338:Everolimus; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008938:Mitosis / Q000502:physiology; D040081:Protein Array Analysis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
C503761:Ccnb2 protein, rat; D018797:Cell Cycle Proteins; D056765:Cyclin B2; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D000068338:Everolimus; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C548796:Cdk1 protein, rat; D018844:Cyclin-Dependent Kinases; D020123:Sirolimus