ABSTRACT-The antinephritic effect of pachyman on original-type anti-GBM nephritis in rats was in vestigated. Pachyman was given to original-type anti-GBM nephritic rats for 10 days from the day of anti-GBM serum injection. Pachyman prevented urinary protein excretion and the elevation of serum cholesterol content. Histopathological observations of the glomeruli indicated that although the number of nuclei and adhesion to capillary walls of Bowman's capsule in nephritic control rats were significantly increased, pachyman reduced the degree of histopathological changes such as hypercellularity and adhe sion as compared to the control group. Although the serum complement CH5() ratio in control group was significantly lower than that in the normal group, the decrease in serum complement CH5o was in hibited by pachyman, and rat C3 deposition in the glomeruli in the pachyman-treated group was signifi cantly reduced. These results suggest that pachyman was effective against original-type anti-GBM nephritis in rats and that the antinephritic mechanisms of pachyman may be partly due to the inhibitory action of this agent on C3 deposition in the glomeruli.

ABSTRACT-Recently we immunohistochemically demonstrated that prostaglandin E2 (PGE2) promoted the clearance of aggregated bovine serum albumin (a-BSA) deposited in glomeruli. Herein, we investigated the role of PGE2 and its signal transduction in the disposal of macromolecules in glomeruli. EP2 and EP4 receptor mRNA was detected in glomeruli by RT-PCR analysis. A-BSA was injected twice into mice. Glomeruli were then isolated and incubated. A-BSA gradually disappeared from isolated glomeruli. PGE 2 increased the intracellular cyclic AMP and decreased a-BSA level in glomeruli. Additionally, 8-bromocyclic AMP evoked a loss of a-BSA in isolated glomeruli. The effect of 8-bromo-cyclic AMP on the clearance of a-BSA was abolished by KT 5720 in glomeruli. PGE2 and 8-bromo-cyclic AMP also prompted disposal of a-BSA in cultured mesangial cells. These findings indicate that PGE2 positively regulates the removal of macromolecules via cyclic AMP and protein kinase A in glomeruli, and they provide insight into how to prevent the development of glomerulonephritis and glomerulosclerosis.

ABSTRACT-Immune complexes in glomeruli are involved in development of diverse glomerulonephritis. The disposal process of glomerular immune complexes has been unclarified. The present studies were un dertaken to determine if thromboxane A2 (TXA2) is associated with the disposal of macromolecules in the glomeruli using mice injected with aggregated bovine serum albumin (a-BSA). A-BSA promptly accumu lated in the glomeruli, the level reaching a plateau at 6 hr after the injection of a-BSA, and then decreased by 48 hr. The production of glomerular TXA2, prostaglandin E2 (PGE2) and prostaglandin 12 concomitantly increased with the decrease of a-BSA in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor an tagonists accelerated clearance of glomerular a-BSA without enhancing renal tissue blood flow. They did not affect a-BSA level in the plasma. In contrast, aminophylline, dopamine and mannitol significantly in creased renal tissue blood flow, but did not decrease glomerular a-BSA. TXA2 synthase inhibitors decreased TXA2 production in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists did not influence the generation of PGE2. The TXA2 analogue U-46619 significantly increased the accumulation of a-BSA in the glomeruli. We propose that TXA2 interferes with the disposal process of aggregated protein in the glomeruli. We also postulate that interception of glomerular activity of TXA2 may be an effective inter vention for managing immune complex-mediated glomerulonephritis and glomerulosclerosis.

Abstract. Prostaglandin E 2 -receptor subtypes, EP 1 , EP 2 , EP 3 , and EP 4 , are present in the kidney. The aim of this study was to elucidate the anti-nephritic effect of an EP 4 -receptor agonist on an experimental nephritic model. Mice were injected i.v. with anti-glomerulus antiserum to induce nephritis. Nephritic glomeruli generated more prostaglandin E 2 (2.6 and 0.7 ng) and less cyclic AMP than normal glomeruli (11 and 26 pmol). The production of cyclic AMP in nephritic glomeruli increased 67% in response to AE1-329, an EP 4 agonist, at 10 −5 M. Nephritic glomeruli expressed a lesser amount of mRNA of prostaglandin E 2 -receptor subtypes as compared with normal glomeruli. AE1-329 was administered s.c. at 100 µg/ kg per day for 3 weeks. AE1-329 suppressed the increase in creatinine and cholesterol compared to those in the control nephritic mice. AE1-329-treated nephritic mice had less crescentic glomeruli and less deposition of rabbit IgG (anti-glomerular basement membrane antibody) in glomeruli than the control mice. AE1-329 prevented the development of glomerulonephritis. These findings suggest that EP 4 -receptor agonists are a promising drug to prevent the development of glomerulonephritis.

-The present study was conducted to investigate the antinephritic effects of berberine and coptisine, which are contained in Coptidis rhizoma, on original-type anti-GBM nephritis in rats. Ber berine and coptisine at the doses of 0.5, 1.0 and 5.0 mg/kg/day, i.p. were effective in inhibiting urinary protein excretion, elevation of serum cholesterol and creatinine contents as well as glomerular histo pathological changes. In addition, berberine at 20 mg/kg/day, p.o. also inhibited urinary protein excre tion throughout the experimental periods. Berberine and coptisine inhibited platelet aggregation in both in vitro and in vivo assays, and berberine inhibited the decline of renal blood flow. Although berberine inhibited an increase in thromboxane B2 formation, it increased the formation of 6-keto-prostaglandin Fl,, in platelets and isolated glomeruli. These results indicate that the antinephritic effects of berberine and coptisine may be partly due to antiplatelet action and improved renal hemodynamics via changing prostanoid synthesis. Keywords:Nephritis, Proteinuria, Berberine, Coptisine, Coptidis rhizomaIt is well-known that Coptidis rhizoma, which is ex tracted from Coptidis japonica MAKINO (Raunucu laceae), has been used as a bitter stomachic drug in Japanese-Chinese herbal medicine prescriptions. Coptidis rhizoma has also been prescribed for the purpose of providing antiphlogistic, analgestic and sedative action. However, it remains unclear which of the components composing Coptidis rhizoma exhibit the pharmacologi cal actions. Recently, Ohtsuka et al. (1) reported on the effects of constituents in the rhizomes of Coptidis japonica MAKING by means of several inflammatroy models. They demonstrated that the principal inhibitory elements acting against an inflammatory response such as granulation tissue formation were berberine and cop tisine.We have reported that TJ-8014, a new Japanese herb al medicine (2-6), and Coptidis rhizoma extract, one of eight crude drugs which constitute TJ-8014 (7), were effective in inhibiting the urinary protein excretion as well as glomerular histopathological changes in several renal diseases. However, it is unclear which compo nents of TJ-8014 have the antinephritic action.Therefore, to clarify the antinephritic effect of ber berine and coptisine, we investigated the effects of ber berine and coptisine on original-type anti-GBM nephri tis in rats in comparison with the effects of dipyrida mole. In the second experiment, the effects of berber ine and coptisine on platelet aggregation and renal blood flow of nephritic control rats were examined to elucidate the antinephritic mechanisms of these compo nents. In the third experiment, we investigated the effects of berberine and coptisine on thromboxane A2 (TXA2) and prostaglandin 12 (PGI2) formations in platelets and isolated glomeruli to determine the mechanisms by which these drugs exert their anti platelet action and improve renal blood flow. MATERIALS AND METHODS AnimalsMale Sprague-Dawley strain SPF rats, weighing approx...