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

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

doi:10.1124/jpet.111.181727

Cited by 29 publications

(24 citation statements)

References 33 publications

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“…Suramin was previously suggested to inhibit fibrotic and growth inhibitory actions of TGF-β 1 and inhibit renal fibrosis [13], [15], [19], [41]. In our study, we found that renal TGF-β 1 and phospho-SMAD-3 protein expressions were elevated in 9 and 17 week old diabetic mice when compared to respective non-diabetic control mice and this increase was more exaggerated in 17 week than 9 week diabetic mice.…”

Section: Discussionsupporting

confidence: 59%

Suramin: A Potential Therapy for Diabetic Nephropathy

et al. 2013

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ObjectiveTo determine whether delayed administration of a single dose of suramin, a drug that has been used extensively in humans to treat trypanosomiasis, attenuates renal injury in a leptin receptor deficient C57BLKS/J db/db type 2 diabetic nephropathy (T2DN) mouse model.Research Design and MethodsGroups of female non-diabetic (control) db/m and diabetic db/db mice of 8 and 16 weeks of age, respectively, were treated with suramin (10 mg/kg) or saline i.v. All animals were euthanized one week later. Measurements in mice 1 week following treatment included the following: body weight; blood glucose; urinary protein excretion; pathological lesions in glomeruli and proximal tubules; changes in protein expression of pro-inflammatory transcription factor nuclear factor κB (NF-κB) and intracellular adhesion molecule-1 (ICAM-1), profibrotic transforming growth factor-β1 (TGF-β1), phospho-SMAD-3 and alpha-smooth muscle actin (α-SMA); and immunohistochemical analysis of leukocyte infiltration and collagen 1A2 (COL1A2) deposition.ResultsImmunoblot analysis revealed increased NF-κB, ICAM-1, TGF-β1, phospho-SMAD-3, and α-SMA proteins in both 9 and 17 week db/db mice as compared to db/m control mice. Immunohistochemical analysis revealed moderate leukocyte infiltration and collagen 1A2 (COL1A2) deposition in 9 week db/db mice that was increased in the 17 week db/db mice. Importantly, suramin significantly decreased expression of all these markers in 9 week db/db mice and partially decreased in 17 week db/db mice without altering body weight, blood glucose or urinary protein excretion. There was no difference in creatinine clearance between 9 week db/m and db/db mice ± suramin. Importantly, in the 17 week db/db mice suramin intervention reversed the impaired creatinine clearance and overt histological damage.ConclusionsDelayed administration of a single dose of suramin in a model of T2DN attenuated inflammation and fibrosis as well as improved renal function, supporting the use of suramin in T2DN.

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Section: Discussionsupporting

confidence: 59%

Suramin: A Potential Therapy for Diabetic Nephropathy

et al. 2013

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“…Suramin was previously suggested to inhibit fibrotic and growth inhibitory actions of TGF-␤ 1 and inhibit renal fibrosis (Liu and Zhuang, 2011;Liu et al, 2011b;Korrapati et al, 2012). In our study, we found that delayed administration of suramin after the induction of diabetes inhibited renal TGF-␤ 1 expression and subsequent SMAD-3 activation in diabetic rats.…”

Section: Downloaded Fromsupporting

confidence: 63%

“…Hyperglycemia is also known to induce activation of mitogen-activated protein kinases (e.g., ERK1/2), the STAT-3 pathway, and/or G proteinmediated aberrant expression of ECM proteins (Marrero et al, 2006;Catania et al, 2007;Tan et al, 2007). These kinases participate in transcriptional up-regulation of collagen and fibronectin in DN (Suzuki et al, 2004;Pang et al, 2010;Liu et al, 2011b). Phosphorylation and subsequent activation of NF-B and STAT-3 were blocked by suramin in diabetic rat kidneys.…”

Section: Downloaded Frommentioning

confidence: 92%

Diabetes-Induced Renal Injury in Rats Is Attenuated by Suramin

Korrapati

Shaner²,

Neely³

et al. 2012

J Pharmacol Exp Ther

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Progression of hyperglycemia-induced renal injury is a contributing factor for diabetic nephropathy (DN)-induced end-stage renal disease (ESRD), and development of novel therapeutic strategies that act early to prevent progression of DN and ESRD are important. We examined the efficacy and mechanism(s) of suramin on hyperglycemia-induced renal injury before development of overt histological damage. Two groups of male Sprague-Dawley rats received streptozotocin (STZ) and one group received saline. Three weeks later, one STZ group received suramin (10 mg/kg). All animals were euthanized 1 week later (4 weeks). Although there was a decrease in creatinine clearance between control and STZ Ϯ suramin rats, there was no difference in creatinine clearance between STZ rats Ϯ suramin intervention. Liquid chromatography-tandem mass spectroscopy-based analysis revealed increases in urinary proteins that are early indicators of DN (e.g., cystatin C, clusterin, cathepsin B, retinol binding protein 4, and peroxiredoxin-1) in the STZ group, which were blocked by suramin. Endothelial intracellular adhesion molecule-1 (ICAM-1) activation, leukocyte infiltration, and inflammation; transforming growth factor-␤1 (TGF-␤1) signaling; TGF-␤1/SMAD-3-activated fibrogenic markers fibronectin-1, ␣-smooth muscle actin, and collagen 1A2; activation of proinflammatory and profibrotic transcription factors nuclear factor-B (NF-B) and signal transducer and activator of transcription factor-3 (STAT-3), respectively, were all increased in STZ rats and suramin blocked these changes. In conclusion, delayed administration of suramin attenuated 1) urinary markers of DN, 2) inflammation by blocking NF-B activation and ICAM-1-mediated leukocyte infiltration, and 3) fibrosis by blocking STAT-3 and TGF-␤1/ SMAD-3 signaling. These results support the potential use of suramin in DN.

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“…Further, delayed administration of suramin was also effective in attenuating the progression of renal fibrosis in obstructive nephropathy [13]. Therefore, there is the potential clinical application of suramin as an anti-fibrotic treatment in patients with chronic kidney disease.…”

Section: Discussionmentioning

confidence: 99%

Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney

Liu

Tolbert

et al. 2012

PLoS ONE

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BackgroundRecently, we demonstrated that suramin, a compound that inhibits the interaction of multiple cytokines/growth factors with their receptors, inhibits activation and proliferation of renal interstitial fibroblasts, and attenuates the development of renal interstitial fibrosis in the murine model of unilateral ureteral obstruction (UUO). However, it remains unclear whether suramin can alleviate glomerular and vascular lesions, which are not typical pathological changes in the UUO model. So we tested the efficacy of suramin in the remnant kidney after 5/6 nephrectomy, a model characterized by the slow development of glomerulosclerosis, vascular sclerosis, tubulointerstitial fibrosis and renal inflammation, mimicking human disease.Methods/Findings5/6 of normal renal mass was surgically ablated in male rats. On the second week after surgery, rats were randomly divided into suramin treatment and non-treatment groups. Suramin was given at 10 mg/kg once per week for two weeks. In the remnant kidney of mice receiving suramin, glomerulosclerosis and vascular sclerosis as well as inflammation were ameliorated. Suramin also attenuated tubular expression of two chemokines, monocyte chemoattractant protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). After renal mass ablation, several intracellular molecules associated with renal fibrosis, including NF-kappaB p65, Smad-3, signal transducer and activator of transcription-3 and extracellular regulated kinase 1/2, are phosphorylated; suramin treatment inhibited their phosphorylation. Futhermore, suramin abolished renal ablation-induced phosphorylation of epidermal growth factor receptor and platelet derived growth factor receptor, two receptors that mediate renal fibrosis.Conclusions and SignificanceThese findings suggest that suramin attenuates glomerular and vascular injury and reduces inflammatory responses by suppression of multiple growth factor receptor-mediated profibrotic signaling pathways. Therefore, suramin may be a useful drug in preventing the fibrosis and sclerosis that characterizes progression of chronic kidney disease.

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

Cited by 29 publications

References 33 publications

Suramin: A Potential Therapy for Diabetic Nephropathy

Suramin: A Potential Therapy for Diabetic Nephropathy

Diabetes-Induced Renal Injury in Rats Is Attenuated by Suramin

Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney

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