Saireito probably prevents mesangial cell proliferation in HIGA mice via PDGF-BB tyrosine kinase inhibition.
BACKGROUND
In this study, we administered saireito to high serum IgA (HIGA) mice and investigated its inhibitory effect on platelet-derived growth factor (PDGF) receptor tyrosine kinase (which causes mesangial proliferation) as one of the possible antinephritic mechanisms of saireito.


METHODS
Female HIGA/NscSlc mice, aged 10 weeks, were divided into five groups (each, n = 12; a control group, three saireito-mixed feed groups, and a captopril-mixed feed group) so that the plasma IgA levels were comparable among the groups. After the grouping, the animals were administered the saireito or captopril, mixed in the feed, until the age of 45 weeks.


RESULTS
At the age of 45 weeks, the glomerular cell number was 47.8 +/- 3.9 / cross section in the HIGA mice in the control group, but 41.6 +/- 2.3 / cross section in the 1.3% saireito-mixed feed group and 38.7 +/- 3.5 / cross section in the captopril-mixed feed group, being significantly lower in both these treatment groups than in the control group. At the age of 45 weeks, the sclerosis score in the HIGA mice in the control group was 0.92 +/- 0.23. However, the sclerosis scores in the 0.26% (0.59 +/- 0.26) and 1.3% (0.58 +/- 0.16) saireito-mixed feed groups were significantly lower than that in the control group. In the captopril-mixed feed group, the sclerosis score was 0.64 +/- 0.34, significantly lower than that in the control group. It was clarified that saireito suppressed mesangial cell proliferation without showing any cytotoxicity. Furthermore, as a result of investigating the mesangial cell proliferation-suppressing effect similarly with the 23 substances constituting saireito, a proliferation-suppressing effect was recognized with isoliquiritigenin (a component of Glycyrrhizae Radix) and oroxylin A (a component of Scutellariae Radix). Oroxylin A and isoliquiritigenin showed an inhibitory effect on PDGF receptor tyrosine kinase. Furthermore, the inhibitory effects of oroxylin A and isoliquiritigenin on tyrosine kinase were found to be specific to the PDGF receptor, and showed no influence on the tyrosine kinase activities of other growth-factor receptors examined.


CONCLUSIONS
These results suggest that the antinephritic effects of saireito in HIGA mice may be partly due to the inhibiton of PDGF tyrosine kinase by oroxylin A and isoliquiritigenin, components of saireito.
Hattori
Tomohisa
T
Tsumura Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Ibaraki, 300-1192, Japan. hattori_tomohisa@mail.tsumura.co.jp.
Sadakane
Chiharu
C
Tsumura Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Ibaraki, 300-1192, Japan.
Koseki
Junichi
J
Tsumura Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Ibaraki, 300-1192, Japan.
Kase
Yoshio
Y
Tsumura Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Ibaraki, 300-1192, Japan.
Takeda
Shuichi
S
Tsumura Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Ibaraki, 300-1192, Japan.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D002216:Captopril / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D047188:Chalcones / Q000302:isolation & purification / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology; D005922:Glomerulonephritis, IGA / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood*; D050527:Mesangial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation
D000806:Angiotensin-Converting Enzyme Inhibitors; D047188:Chalcones; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D007070:Immunoglobulin A; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; C080903:sairei-to; D000077214:Becaplermin; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D002216:Captopril; C040920:isoliquiritigenin; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor