The Role of Protein Kinase C in Kidney Toxicity by New Immunosuppressant

1995 Fiscal Year Final Research Report Summary

• Project/Area Number: 06454456
• Research Category: Grant-in-Aid for General Scientific Research (B)
• Allocation Type: Single-year Grants
• Research Field: Urology
• Research Institution: Yamanashi Medical University
• Principal Investigator: UENO Akira Yamanashi Medical Univ., Faculty of Medicine, Professor, 医学部, 教授 (30010193)
• Co-Investigator(Kenkyū-buntansha): KUBODERA Satoshi Yamanashi Medical Univ., Faculty of Medicine, Research Associate, 医学部, 助手 (90195511) ; TAGO Kiichiro Yamanashi Medical Univ., Faculty of Medicine, Lecturer, 医学部, 講師 (60126117)
• Project Period (FY): 1994 – 1995
• Keywords: Protein Kinase C / immunosuppressant / kidney toxicity

Research Abstract

FK-506 does the extremely similar action of immunity control as cyclosporine A. Recently, the research on the mechanism of immunity control has advanced increasingly. If FK-506 enters T-cell, it will combine with FK-506-binding protein, immunophilin. It is thought that this FK-506-immunophilin complex impedes calcineurin by Ca++ and calmodulin, and that it controls the function of T-cell and demonstrates the action of immunity control. However, this medicine poses problems about the kidney toxicity in many cases, because the concentration in effective blood and the one in side-effects region are especially close. And then, we examine the possibility of participation of proteinkinaseC (PKC) in kidney organization, with SD-rat.
Specifically, we extract FK-506 medication groups in the abdominal cavity (2.5 mg/g weight medication group, 5.0 mg/g weight medication group) immediately after slaughtering the kidney of the contrast medication group, and divid them into kidney cortex and kidney m arrow on the ice. Then, we measure and compare PKC activity of extracted liquid of each organization, Bmax (total amount of PKC) and Kd(separative constant) as the phorbolester receptor of each organization extracted liquid. At present, Bmax (total amount of PKC) of FK-506 (5.0mg/g weight) medication group shows lower tendency than a contrast group, but it is not significant difference. As for PKC activity, there is no difference between FK-506 medication groups in the abdominal cavity and contrast groups. Considering about causes of these, there are possibilities such as the lack of the amount of FK-506 medication or the difference of the action mechanism from cyclosporine A. Besides, at present, it is confirmed that PKC has at least seven kinds of isozymes, so that FK-506 medication does not always make change in all kinds of isozymes but makes change only in some kinds of isozyme.
We will continue this research, furthermore. We possibly need to experiment by dividing PKC isozyme with chromatography.