Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

Liu, Na; Tolbert, Evelyn; Pang, Maoyin; Ponnusamy, Murugavel; H, Yan; Zhuang, Songlin

doi:10.1681/asn.2010090956

Cited by 76 publications

(74 citation statements)

References 49 publications

(59 reference statements)

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“…30 A similar finding has been observed in UUO kidneys. 22 In support of this finding, we demonstrated that TbRII expression is significantly increased by UUO and that the treatment with 17AAG effectively prevents the enhancement of TbRII abundance.…”

Section: Hsp90 Inhibitor Reduces Renal Fibrosis H Noh Et Alsupporting

confidence: 75%

“…4,5 Upregulation of TGF-b1 is a common finding in virtually every type of progressive chronic kidney disease, in both animals and humans. In cell culture systems, TGF-b1 stimulates mesangial cells, 21 interstitial fibroblasts, 22,23 and tubular epithelial cells 9,10,24 and induces matrix expression through its interaction with TGF-b receptors. Thus, TGF-b1 has been studied as a target to prevent the progression of renal fibrosis.…”

Section: Hsp90 Inhibitor Reduces Renal Fibrosis H Noh Et Almentioning

confidence: 99%

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Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor

Noh

Kim²,

Yu³

et al. 2012

Laboratory Investigation

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The accumulation of extracellular matrix proteins in the interstitial area is the final common feature of chronic kidney diseases. Accumulating evidence suggests that transforming growth factor (TGF)-b1 promotes the development of renal fibrosis. Heat shock protein (Hsp) 90 inhibitors have been shown to repress TGF-b1 signaling, but whether they inhibit renal fibrosis is unknown. The purpose of this study is to determine the therapeutic efficacy of Hsp90 inhibitor on renal fibrosis. In TGF-b1-treated HK2 cells and unilateral ureteral obstruction (UUO) kidneys, we found that 17-allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, decreased the expression of a-smooth muscle actin, fibronectin, and collagen I and largely restored the expression of E-cadherin. 17AAG inhibited TGF-b1-mediated phosphorylation of Smad2, Akt, glycogen synthase kinase-3b, and extracellular signal-regulated kinase in HK2 cells. Inhibition of Hsp90 also blocked TGF-b1-mediated induction of snail1. This 17AAG-induced reduction was completely restored by simultaneous treatment with proteasome inhibitor MG132. Furthermore, 17AAG blocked the interaction between Hsp90 and TGF-b type II receptor (TbRII) and promoted ubiquitination of TbRII, leading to the decreased availability of TbRII. Smurf2-specific siRNA reversed the ability of 17AAG to inhibit TGF-b1 signaling. The effect of 17AAG on TbRII expression and renal fibrosis was confirmed in UUO kidneys. These findings suggest that Hsp90 inhibitor prevents the development of renal fibrosis via a mechanism dependent on Smurf2-mediated degradation of TbRII.

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Section: Hsp90 Inhibitor Reduces Renal Fibrosis H Noh Et Alsupporting

confidence: 75%

Section: Hsp90 Inhibitor Reduces Renal Fibrosis H Noh Et Almentioning

confidence: 99%

Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor

Noh

Kim²,

Yu³

et al. 2012

Laboratory Investigation

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“…In a recent study, we found that suramin is effective in preventing the onset of renal fibrosis in a model of obstructive nephropathy when given immediately after surgical ligation of the ureter (Liu et al, 2011). In the present study, we further demonstrate that delayed administration of a single dose of suramin after UUO injury inhibits further increases in renal fibrosis as indicated by reduced deposition of ECM components and expression of type I collagen and fibronectin.…”

Section: Discussionsupporting

confidence: 78%

“…Here, we have shown that suramin is able to halt progressive renal fibrosis in a mouse model when given early after UUO injury. Our recent studies also show that suramin inhibited the progression of renal fibrosis and prevented renal function impairment in a rat model of remnant kidney disease (Liu et al, 2011). Therefore, suramin might be an interesting drug candidate for treating patients with CKD.…”

Section: Suramin Inhibits Progression Of Renal Fibrosis 763mentioning

confidence: 70%

“…Furthermore, suramin can prevent coronary restenosis after percutaneous transluminal coronary angioplasty (Urasawa et al, 2001). In a recent study, we also assessed the effect of suramin on the development of renal fibrosis in animal models of obstructive nephropathy and remnant kidney diseases and demonstrated that it was effective in inhibiting renal fibrosis when given before initiation of renal fibrosis (Liu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

Liu

Tolbert²,

Ponnusamy³

et al. 2011

J Pharmacol Exp Ther

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We recently showed that suramin treatment prevents the onset of renal fibrosis in a model of obstructive nephropathy induced by unilateral ureteral obstruction (UUO). In this study, we further assessed the effect of delayed administration of suramin on the progression of tubulointerstitial fibrosis. Mice were given a single dose of suramin at 20 mg/kg starting at day 3 of obstruction, and kidneys were harvested after an additional 7 or 14 days of obstruction. Suramin completely blocked further increase in expression of type I collagen and fibronectin and largely suppressed expression of ␣-smooth muscle actin (␣-SMA) in both treatment groups. UUO injury induced phosphorylation of Smad-3, a key mediator of transforming growth factor-␤ (TGF-␤) signaling, epidermal growth factor receptor, and platelet-derived growth factor receptor after 3 days and further increased at 10 days after UUO injury. When suramin was administered at 3 days after obstruction, phosphorylation of these molecules was not further increased in the obstructed kidney. Suramin treatment also inhibited activation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1 and 2, two signaling pathways associated with renal fibrogenesis. Furthermore, delayed application of suramin suppressed TGF-␤1-induced expression of ␣-SMA and fibronectin in cultured renal interstitial fibroblasts. These results indicate that administration of suramin is effective in attenuating the progression of renal fibrosis after injury and suggest the potential clinical application of suramin as an antifibrotic treatment in patients with chronic kidney disease.

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Suramin attenuates dystrophin‐deficient cardiomyopathy in the mdx mouse model of duchenne muscular dystrophy

et al. 2013

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Suramin Inhibits Renal Fibrosis in Chronic Kidney Disease

Cited by 76 publications

References 49 publications

Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor

Heat shock protein 90 inhibitor attenuates renal fibrosis through degradation of transforming growth factor-β type II receptor

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

Suramin attenuates dystrophin‐deficient cardiomyopathy in the mdx mouse model of duchenne muscular dystrophy

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