Abstract
The present study was performed to investigate the effects of the antiallergic drug tranilast on the development of diabetic nephropathy in streptozotocin (50 mg/kg)-induced diabetic spontaneously hypertensive rats (SHR). Diabetic SHR were given standard chow or chow containing tranilast at a dose of 1400 mg/kg for 24 weeks. The effects of tranilast on urinary albumin excretion, mesangial expansion, expression of transforming growth factor-β (TGF-β) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-β and 8-hydroxy-2′-deoxyguanosine (8-OHdG) excretion were assessed. Tranilast did not affect the blood glucose concentration or blood pressure in diabetic SHR. Urinary albumin excretion rate and creatinine clearance were markedly increased in diabetic SHR. Tranilast treatment decreased albuminuria and hyperfiltration. Tranilast inhibited the diabetes-induced expansion of mesangial and tuft areas, as well as the increase in urinary TGF-β and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-β as determined immunohistochemically. The levels of TGF-β and type I collagen mRNA expression were increased in the renal cortex in untreated diabetic SHR at 24 weeks, as determined by real-time quantitative polymerase chain reaction. Tranilast treatment inhibited the up-regulation of TGF-β and type I collagen mRNA expression by 65 and 36%, respectively, in diabetic SHR. In conclusion, tranilast decreased albuminuria by suppressing glomerular hyperfiltration, mesangial expansion, and loss of the charge barrier via regulation of extracellular matrix gene expression and oxidative stress. Tranilast may be clinically useful in the treatment of diabetic nephropathy.
Footnotes
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doi:10.1124/jpet.105.084772.
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ABBREVIATIONS: GBM, glomerular basement membrane; TGF-β, transforming growth factor-β; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; SHR, spontaneously hypertensive rat(s); SBP, systolic blood pressure; Cr, creatinine; Ccr, creatinine clearance; LRE, lamina rara externa; PCR, polymerase chain reaction; ECM, extracellular matrix; PKC, protein kinase C; AGE, advanced glycation end product.
- Received February 9, 2005.
- Accepted April 20, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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