Suppressive mechanisms of Sairei-to on mesangial matrix expansion in rat mesangioproliferative glomerulonephritis.
BACKGROUND
Sairei-to (TJ-114) is a Japanese herbal medicine of standardized quality, originating from traditional Chinese medicine. In the present in vivo study, we investigated the suppressive effects of TJ-114 and related drugs, Shosaiko-to (TJ-9), and Saiboku-to (TJ-96), on mesangioproliferative glomerulonephritis (MsPGN) in rats. TJ-9 is a basal prescription of TJ-96 and TJ-114. We evaluated the efficacy of these drugs on proteinuria, extracellular matrix (ECM) accumulation, and superoxide dismutase (SOD)-activity.


METHODS
MsPGN in Wistar rats was induced by intravenous injection of rabbit anti-rat thymocyte serum (ATS). TJ-114, TJ-9, TJ-96 (500 mg/kg/day), or prednisolone (PSL, 2 mg/kg/day) was orally administered to the rats as drinking water from the day of ATS injection (day 0) to day 8, when rats were sacrificed and the kidney specimens were collected. Macrophage infiltration was evaluated by immunostaining for ED-1. ECM was measured by trichrome-staining, and fibronectin immunostaining. Northern blotting was performed to clarify the mRNA expression of cytokines and fibronectin. SOD-activity in the homogenate of renal cortex was also evaluated.


RESULTS
The amount of urinary protein was significantly decreased only in the TJ-114-treated group compared with the disease control group (p < 0.05). The number of ED-1-positive cells was significantly decreased in all the treatment groups (p < 0.05, respectively). Decreases in the trichrome-stained area were observed moderately in the TJ-114-treated group (66% of control, p < 0.001) and mildly in the PSL-treated group (76% of control, p < 0.001). The staining area of fibronectin in the glomerulus was significantly decreased in all the treated groups except PSL, and was especially suppressed in the TJ-114-treated group (45% of control, p < 0.001). Transforming growth factor (TGF) and connective tissue growth factor (CTGF) expression significantly decreased in the TJ-114-treated group to the control level (p < 0.05). TGF-beta, CTGF, and fibronectin mRNA were upregulated in the disease control group, and TJ-114 suppressed these mRNA expressions in glomeruli. The SOD-activity of renal cortex-homogenate was significantly augmented in all the treated groups except PSL, markedly in the TJ-96- and TJ-114-treated groups.


CONCLUSIONS
These results suggest that TJ-114 ameliorates ECM accumulation in experimental rat MsPGN, partly suppressing TGF-beta and CTGF expression through the recovery of SOD-activity.
Ono
Takahiko
T
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. ono@u-shizuoka-ken.ac.jp
Liu
Ning
N
Makino
Toshiaki
T
Nogaki
Fumiaki
F
Muso
Eri
E
Honda
Gisho
G
Kita
Toru
T
D000818:Animals; D055513:Connective Tissue Growth Factor; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism*; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007672:Kidney Cortex / Q000502:physiology; D008264:Macrophages; D008297:Male; D011507:Proteinuria; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D015854:Up-Regulation
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D004365:Drugs, Chinese Herbal; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C080903:sairei-to; D055513:Connective Tissue Growth Factor; D013482:Superoxide Dismutase