The Effects of a Selective CK2 Inhibitor on Anti-glomerular Basement Membrane Glomerulonephritis in Rats.
Protein kinase CK2 ("casein kinase II") is a protein serine/threonine kinase that plays critical roles in biological processes such as cell growth, cell cycle progression, and apoptosis. So far, we have identified that one catalytic isozyme of CK2, CK2α, is over-expressed in the kidney during the progression of glomerulonephritis (GN). Moreover, we have shown that in vivo inhibition of CK2 by administration of CK2 inhibitors was effective in the treatment of experimental GN. Hence the development of potent CK2 inhibitors should be considered in therapeutic strategies for GN. In the present study we identified compound 13, a pyrazine derivative, as a potent CK2 inhibitor. By performing enzyme kinetics analysis in vitro, we characterized the inhibition of compound 13 toward each CK2 catalytic isozyme. Furthermore, in vivo, we demonstrated that compound 13 is effective in attenuating proteinuria, decreasing the enhanced level of blood urea nitrogen and serum creatinine, and ameliorating glomerular crescent formation in an experimental GN rat model. On the other hand, cellular apoptosis was detected in the rat testis following administration of compound 13. This study provides clues for new strategies for developing applicable compounds into CK2-targeted GN treatments.
Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University.
Junfeng
J
Shi
Ning
N
Liu
Ying
Y
Xiao
Yoshinori
Y
Takei
Misato
M
Yasue
Yamato
Y
Suzuki
Zengye
Z
Hou
Hiroaki
H
Ohno
Masateru
M
Yamada
Nobuhiro
N
Fuchi
Keiyu
K
Oshida
Yohei
Y
Miyamoto
Gozoh
G
Tsujimoto
Akira
A
Hirasawa
D000818:Animals; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004642:Emodin / Q000494:pharmacology / Q000627:therapeutic use; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011921:Rats, Inbred WKY; D013737:Testis / Q000187:drug effects / Q000473:pathology
D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D003404:Creatinine; D047390:Casein Kinase II; D004642:Emodin