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      Therapeutic Mechanism of Saikosaponin-d in Anti-Thy1 mAb 1-22-3-Induced Rat Model of Glomerulonephritis

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          Aims: Mesangioproliferative glomerulonephritis is a common kidney disease and at present, there is no effective treatment. Our previous studies have demonstrated that Sairei-to can significantly prevent progression of experimental glomerulonephritis in rats. Although we have reported that the active component of Sairei-to in treatment of glomerulonephritis was Saikosaponin-d (Ssd), mechanism of Ssd in prevention of mesangioproliferative glomerulonephritis progression is still unknown. Therefore, current study examines the effects of Ssd on progression of mesangioproliferative glomerulonephritis induced by anti-Thy1 monoclonal antibody 1-22-3 (mAb 1-22-3) in uninephrectomized rats. Methods: Eighteen female Wistar rats first received uninephrectomy and mAb 1-22-3 injection and were then divided into 3 groups: treated daily with phosphate-buffered saline (PBS), 0.6 or 1.8 mg/kg of Ssd. Urinary protein concentration and systolic blood pressure were evaluated and the kidneys were collected and subjected to histological and immunohistological evaluation. The mRNA and protein of the kidneys were extracted and subjected to reverse transcriptase polymerase chain reaction and Western blot analysis, respectively. Results: Ssd reduced the amount of urinary protein and systolic blood pressure. Ssd administration also decreased extracellular matrix expansion, crescentic formation as well as infiltration of macrophages and CD8+ T lymphocytes. Moreover, Ssd significantly reduced expression of transforming growth factor beta 1 (TGF-β1) and type I collagen in the kidneys. Conclusion: Ssd inhibits the progression of mesangioproliferative glomerulonephritis through reduction of the expression of TGF-β1 and the infiltration of macrophages and CD8+ T lymphocytes.

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          Most cited references 24

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          Transforming growth factor beta in tissue fibrosis.

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            Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats.

            Hypertension frequently accompanies chronic glomerulonephritis. Mesangial injury and glomerulosclerosis are common in glomerulonephritis and are often harbingers of progressive glomerular destruction. Thus, in a model of mesangial immune injury we studied the relationship between hypertension, mesangial injury, and glomerulosclerosis. We induced mesangial ferritin-antiferritin immune complex disease (FIC) in Dahl salt-sensitive (S) and salt-resistant (R) rats. S and R rats with FIC were fed chow containing 0.3% NaCl until 14 weeks of age and then switched to 8.0% NaCl chow until 28 weeks of age. Groups of control S and R rats (no FIC) were either fed 0.3% NaCl for 28 weeks or switched to 8.0% NaCl chow at 14 weeks of age. Blood pressure, serum creatinine, urinary protein, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined at 14 and 28 weeks of age. R rats with or without FIC did not develop hypertension; mesangial injury was minimal. At 14 weeks of age, only S FIC rats developed hypertension, proteinuria, significant mesangial expansion and early glomerulosclerosis. At 28 weeks of age, proteinuria, mesangial expansion, and glomerulosclerosis were significantly more severe in hypertensive S rats with FIC than in those without FIC. These studies show that despite a normal salt intake, mesangial injury hastened the onset of hypertension, but only in rats genetically predisposed to hypertension (S FIC at 14 weeks). High dietary salt further aggravated hypertension, which, in turn, magnified both mesangial injury and glomerulosclerosis. Clinically, the different rates of progression of human glomerulonephritis associated with hypertension may be in part dependent on similar mechanisms.
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              Effect of castration and sex hormone treatment on survival, anti- nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice

              NZB/NZW F1 mice of both sexes were castrated at 2 wk of age and implanted subcutaneously with silastic tubes containing either 5-alpha- dihydrotestosterone or estradiol-17-beta. Mice receiving androgen showed improved survival, reduced anti-nucleic acid antibodies, or less evidence of glomerulonephritis as determined by light, immunofluorescent, and electron microscopy. By contrast, opposite effects were observed in castrated mice receiving estrogen. Intact male NZB/NZW F1 mice received androgen implants at 8 mo, an age when they develop an accelerated autoimmune disease associated with a decline in serum testosterone concentration. Such treated mice had improved survival and reduced concentrations of antibodies to DNA and to polyadenylic acid (Poly A). Prepubertal castration of male NZB/NZW F1 mice results in an earlier appearance of IgG antibodies to Poly A. This effect of castration was prevented if neonatal thymectomy was also performed.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                December 2005
                12 August 2005
                : 101
                : 4
                : e111-e118
                aDepartment of Pharmacology, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China; bFaculty of Pharmacy, University of Manitoba, Winnipeg, Canada; cDepartment of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
                87437 Nephron Exp Nephrol 2005;101:e111–e118
                © 2005 S. Karger AG, Basel

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                Figures: 5, References: 39, Pages: 1
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