Tranilast Slows the Progression of Advanced Diabetic Nephropathy

Soma, Jun; Sugawara, Takashi; Huang, Yee-Der; Nakajima, Jun; Kawamura, Minoru

doi:10.1159/000064071

Cited by 49 publications

(34 citation statements)

References 26 publications

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“…Recently, a small pilot study in diabetic patients with advanced diabetic nephropathy demonstrated that tranilast significantly reduced the rate of decline of glomerular filtration rate with a trend toward reduction in proteinuria (Soma et al, 2002). Our findings suggest that tranilast has beneficial effects on early events in the development of diabetic nephropathy even with hypertension.…”

Section: Discussionsupporting

confidence: 53%

Tranilast Prevents the Progression of Experimental Diabetic Nephropathy through Suppression of Enhanced Extracellular Matrix Gene Expression

Akatsuka¹,

Ota²,

Torita³

et al. 2005

J Pharmacol Exp Ther

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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-␤ (TGF-␤) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-␤ and 8-hydroxy-2Ј-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-␤ and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-␤ as determined immunohistochemically. The levels of TGF-␤ 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-␤ 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.

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Section: Discussionsupporting

confidence: 53%

Tranilast Prevents the Progression of Experimental Diabetic Nephropathy through Suppression of Enhanced Extracellular Matrix Gene Expression

Akatsuka¹,

Ota²,

Torita³

et al. 2005

J Pharmacol Exp Ther

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“…Whether this is due to inhibition of Alk5 activity or due to suppression of TGF-␤1-stimulated p38 MAP kinase remains to be determined. Tranilast, a pharmaceutical compound that has been used in animal models of fibrotic disease (40) and in human subjects to treat keloids and to prevent vascular restenosis (33), abrogated both TGF-␤1-stimulated nodule formation and monolayer ECM accumulation (Fig. 7, B and C), at doses similar to those reported to have antiproliferative effects in leiomyoma cells (39).…”

Section: Resultsmentioning

confidence: 77%

In vitro models of TGF-β-induced fibrosis suitable for high-throughput screening of antifibrotic agents

Norman²,

Shrivastav³

et al. 2007

American Journal of Physiology-Renal Physiology

111

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Progressive fibrosis is a cause of progressive organ dysfunction. Lack of quantitative in vitro models of fibrosis accounts, at least partially, for the slow progress in developing effective antifibrotic drugs. Here, we report two complementary in vitro models of fibrosis suitable for high-throughput screening. We found that, in mesangial cells and renal fibroblasts grown in eight-well chamber slides, transforming growth factor-β1 (TGF-β1) disrupted the cell monolayer and induced cell migration into nodules in a dose-, time- and Smad3-dependent manner. The nodules contained increased interstitial collagens and showed an increased collagen I:IV ratio. Nodules are likely a biological consequence of TGF-β1-induced matrix overexpression since they were mimicked by addition of collagen I to the cell culture medium. TGF-β1-induced nodule formation was inhibited by vacuum ionized gas treatment of the plate surface. This blockage was further enhanced by precoating plates with matrix proteins but was prevented, at least in part, by poly-l-lysine (PLL). We have established two cell-based models of TGF-β-induced fibrogenesis, using mesangial cells or fibroblasts cultured in matrix protein or PLL-coated 96-well plates, on which TGF-β1-induced two-dimensional matrix accumulation, three-dimensional nodule formation, and monolayer disruption can be quantitated either spectrophotometrically or by using a colony counter, respectively. As a proof of principle, chemical inhibitors of Alk5 and the antifibrotic compound tranilast were shown to have inhibitory activities in both assays.

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“…In the context of the recent pilot study in humans, this study suggests that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring (28).…”

Section: Discussionmentioning

confidence: 87%

“…In two other studies, the effects of tranilast in diabetic nephropathy were examined. In the first, a pilot study of nine humans with advanced diabetic nephropathy, tranilast was reported to slow the decline in GFR over a 12-mo period, with a nonsignificant trend toward reduction in proteinuria (28). More recently, tranilast was also shown to reduce renal fibrosis and proteinuria in an experimental model of advanced diabetic nephropathy when used as a late intervention (9).…”

Section: Discussionmentioning

confidence: 99%

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

Kelly

Zhang

Gow

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Pathologic fibrosis is a key feature of progressive renal disease that correlates closely with kidney dysfunction and in which the prosclerotic growth factor TGF-␤ has been consistently implicated. anthranilic acid), an antifibrotic agent that is used to treat hypertrophic scars and scleroderma, has also been shown to inhibit TGF-␤-induced extracellular matrix synthesis in a range of cell types, including those of renal origin. Therefore, the effects of tranilast on kidney fibrosis and dysfunction were examined in the subtotal nephrectomy model of progressive renal injury. Subtotal nephrectomy led to proteinuria and renal dysfunction in association with glomerulosclerosis, tubulointerstitial fibrosis, and macrophage accumulation. Despite persistent hypertension, treatment with tranilast led to a reduction in albuminuria (61.7 ϫ/Ϭ 1.2 versus 20.5 ϫ/Ϭ 1.3 mg/d; P Ͻ 0.01) and plasma creatinine (0.16 versus 0.08 mmol/L; P Ͻ 0.01) in subtotally nephrectomized rats. In addition, features suggestive of TGF-␤ activation, including glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and macrophage accumulation, all were significantly attenuated by tranilast in association with evidence of reduced TGF-␤ signaling in vivo.In the context of a recent pilot study in humans, the findings of the present report suggest that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring.

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Tranilast Slows the Progression of Advanced Diabetic Nephropathy

Cited by 49 publications

References 26 publications

Tranilast Prevents the Progression of Experimental Diabetic Nephropathy through Suppression of Enhanced Extracellular Matrix Gene Expression

Tranilast Prevents the Progression of Experimental Diabetic Nephropathy through Suppression of Enhanced Extracellular Matrix Gene Expression

In vitro models of TGF-β-induced fibrosis suitable for high-throughput screening of antifibrotic agents

Tranilast Attenuates Structural and Functional Aspects of Renal Injury in the Remnant Kidney Model

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