Abstract
Oxidative stress has been proposed as the basis for the pathogenesis of diabetic nephropathy. Rebamipide is a novel antiulcer drug that has, in addition, oxygen radical scavenging activity. Our study examines whether rebamipide could ameliorate the pathophysiology associated with experimental diabetes in vivo, such as microalbuminuria, and to reverse the increased production of transforming growth factor-β1 and fibronectin in SV-40 transformed murine mesangial cells in culture that were stimulated with high glucose. Chronic administration of rebamipide (100 mg/kg/day, p.o., for 3 wk) to rats, in which diabetes was previously induced by the i.v. injection of streptozotocin 50 mg/kg, reversed hyperglycemia, which would contribute to prevent the increases in urinary excretion rates of albumin and lipid peroxides observed in this experimental model. Rebamipide, at this dose level, did not cause any discernible effect on age-matched control rats. Rebamipide 2 mM was as effective as 20 mM of dimethylthiourea, a known hydroxyl radical scavenger, in inhibiting the increase in lipid peroxides, transforming growth factor-β1, fibronectin mRNAs and proteins induced by incubation of cultured mesangial cells with high glucose. Our data suggest that rebamipide attenuates high glucose-induced nephropathy, which is attributable, in part, to its antioxidative property and, in part, to its effect on reversing hyperglycemia.
Footnotes
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Send reprint requests to: Dr. Kyung Hwan Kim, Department of Pharmacology, Yonsei University College of Medicine, Seoul 120-752, Korea.
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↵1 This study was supported in part by a grant from the Korea Otsuka Pharmaceutical Co., Ltd., Seoul, Korea and by a grant from Korea Science and Engineering Foundation (KOSEF 94-0403-07-01-3).
- Abbreviations:
- CR
- control rats
- DMEM
- Dulbecco’s modified Eagle’s media
- DMTU
- dimethylthiourea
- EDTA
- ethylenediamine tetraacetic acid, FBS, fetal bovine serum
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- HEPES
- N-2-hydroxyethylpiperazine-N’-2-ethane sulfonic acid
- LPO
- lipid peroxides
- PBS
- phosphate buffered saline
- SDS
- sodium dodecyl sulfate
- SSC
- sodium chloride and sodium citrate
- STZR
- streptozotocin induced diabetic rats
- TGF-β1
- transforming growth factor-β1
- Received September 25, 1996.
- Accepted February 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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