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1.
Nephron Physiol ; 97(4): p58-65, 2004.
Article in English | MEDLINE | ID: mdl-15331931

ABSTRACT

AIMS: Effects of the blockade of renin-angiotensin system (RAS), by angiotensin-converting enzyme inhibitor (ACEi), type 1 angiotensin II receptor blocker (ARB), or a combination of both, were evaluated in Adriamycin (ADR)-induced glomerulopathy. METHODS: Male Sprague-Dawley rats (180-250 g) were induced of glomerulopathy by treatment with ADR (2 mg/kg, i.v.). Six weeks later, they were treated with cilazapril (1 mg/kg/day) and/or losartan (10 mg/kg/day) for an additional 6 weeks. RESULTS: The urinary excretion of protein progressively increased following the treatment with ADR, which was prevented by ACEi, ARB, and a combination of both. Similarly, the glomerulopathy assessed by glomerulosclerosis index was also ameliorated by ACEi or ARB. However, combined therapy of both ACEi and ARB was without an additional effect (Control 1.4 +/- 0.4%, ADR 10.7 +/- 2.7%**, ACEi 0.8 +/- 0.4%, ARB 2.6 +/- 1.0%, ACEi+ARB 1.7 +/- 1.5%, ** p < 0.01 vs. Control). The expression of transforming growth factor-beta(1) was increased following the treatment with ADR (1.4 +/- 0.07-fold, p < 0.05 vs. Control), however, the degree of which was similarly blunted by either ACEi, ARB, or the combination of both. The expression of type 1 angiotensin II receptor mRNA increased following the treatment with ADR, the degree of which was further upregulated by ACEi and decreased by ARB to the control level (ADR 1.3 +/- 0.06-fold*, ACEi 1.8 +/- 0.05-fold***, ARB 1.0 +/- 0.04-fold, * p < 0.05 and *** p < 0.001 vs. Control). The combined therapy of ACEi and ARB still showed an upregulation of type 1 angiotensin II receptor mRNA, however, of which degree was mitigated compared with that induced by ACEi alone (ACEi+ARB 1.5 +/- 0.04-fold, ** p < 0.01 vs. Control). On the contrary, the expression of type 2 angiotensin II receptor mRNA was downregulated following the treatment with ADR, which was similarly restored to the control level by ACEi, ARB, and a combination of both (ADR 0.5 +/- 0.08-fold**, ACEi 1.0 +/- 0.06-fold, ARB 1.0 +/- 0.05-fold, ACEi+ARB 1.0 +/- 0.05-fold, ** p < 0.01 vs. Control). CONCLUSION: It is suggested that combined therapy of ACEi and ARB with relatively high or maximal doses of each drug has no additive or synergistic benefits on the progression of ADR-induced glomerulopathy. Effects of RAS blockade may in part be related to differential regulation of type 1 and type 2 angiotensin II receptors.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cilazapril/therapeutic use , Doxorubicin/toxicity , Glomerulosclerosis, Focal Segmental/prevention & control , Losartan/therapeutic use , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Blood Pressure/drug effects , Cilazapril/administration & dosage , Cilazapril/pharmacology , Drug Interactions , Drug Synergism , Gene Expression Regulation/drug effects , Glomerulosclerosis, Focal Segmental/chemically induced , Glomerulosclerosis, Focal Segmental/pathology , Losartan/administration & dosage , Losartan/pharmacology , Male , Nephrosis, Lipoid/chemically induced , Nephrosis, Lipoid/pathology , Nephrosis, Lipoid/prevention & control , Proteinuria/drug therapy , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1/biosynthesis , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 2/biosynthesis , Receptor, Angiotensin, Type 2/genetics , Renin-Angiotensin System/drug effects , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1
2.
Immunol Lett ; 90(2-3): 93-6, 2003 Dec 15.
Article in English | MEDLINE | ID: mdl-14687710

ABSTRACT

Chronic rheumatoid arthritis (RA) is characterized by the hyperplasia of synovial tissue, which results from dysregulation of proliferative and antiapoptotic signals transduced in the synovial cells by unknown mechanisms. To identify candidate factors involved in the regulation of synovial hyperplasia, the expression profile of 205 apoptosis-related genes was compared between tissues from patients with RA and osteoarthritis (OA) using a cDNA microarray. Upregulated genes in the RA synovium included TNFR2, FLICE2, and signaling molecules involved in a MAP kinase pathway (GRB2, MAPK p38). In contrast, genes encoding SARP1 and various cell cycle regulators were down-regulated in the RA synovium relative to OA. Importantly, the expression levels of GRB2 and FLICE2 genes were remarkably enhanced in RA synoviocytes but not in OA synoviocytes in response to tumor necrosis factor (TNF)-alpha treatment. Thus, these results suggest that over-expression of GRB2 and FLICE2 in RA synovium is caused by TNF-alpha inducibility differentially regulated in RA synoviocytes and provide potential pathogenic roles of these genes in the hyperplasia of the RA synovium.


Subject(s)
Adaptor Proteins, Signal Transducing , Arthritis, Rheumatoid/genetics , Caspases/genetics , Gene Expression Regulation/drug effects , Proteins/genetics , Synovial Membrane/drug effects , Synovial Membrane/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Caspase 10 , Cells, Cultured , GRB2 Adaptor Protein , Gene Expression Profiling , Humans , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Synovial Membrane/pathology
3.
J Med Food ; 6(4): 337-43, 2003.
Article in English | MEDLINE | ID: mdl-14977442

ABSTRACT

This study compared the ability of genistein, a soy isoflavone, with that of 17 beta-estradiol to prevent bone loss in cadmium (Cd)-exposed ovariectomized (OVX) rats during growth. Female Wistar rats (4 weeks old) were either sham-operated (SH; n = 9/group) or OVX and placed on experimental diets (n = 9/group): OVX; OVX rats fed 50 ppm of CdCl(2) (OVX-Cd); OVX fed 50 ppm of CdCl(2) and 10 microg/kg of body weight genistein (OVX-Cd-G); and OVX fed 50 ppm of CdCl(2) and 10 microg/kg of body weight estrogen (OVX-Cd-E). All rats were given free access to AIN-76 modified diet and drinking water, with or without Cd, for 8 weeks. The OVX groups gained more body weight than the SH group. Femoral weight was increased by feeding genistein and estradiol, whereas femoral length among groups was not significantly different. Femoral Cd content was significantly higher in the OVX-Cd group than in the other groups. Both serum osteocalcin and calcium (Ca) concentrations, as well as urinary Ca, were significantly higher in the OVX-Cd group than in the other groups. Urinary excretion of Cd was significantly increased in Cd-OVX-G rats, and fecal Cd excretion was increased by feeding both genistein and estradiol. Femoral histomorpological changes in proliferative cartilage and hypertrophic cells in the OVX-Cd group showed that both cell types were decreased by feeding Cd, and irregular arrangements were observed in proliferative cells. However, both cells types exhibited normal distribution in OVX-Cd-G and OVX-Cd-E groups. These findings suggest that Cd/OVXinduced osteopenia or osteoporosis probably results from an increase in bone turnover. Genistein may be involved in stimulating Cd excretion and inhibiting Ca excretion from bone.


Subject(s)
Bone Density/drug effects , Bone Diseases, Metabolic/chemically induced , Bone and Bones/metabolism , Cadmium/metabolism , Genistein/pharmacology , Animals , Bone Diseases, Metabolic/prevention & control , Cadmium/urine , Calcium/blood , Calcium/urine , Estradiol/pharmacology , Female , Growth Inhibitors/pharmacology , Humans , Osteoporosis, Postmenopausal/prevention & control , Ovariectomy , Random Allocation , Rats , Rats, Wistar , Weight Gain/drug effects
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