Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney Na Liu1,2, Song He1,3, Evelyn Tolbert2, Rujun Gong 2 , George Bayliss2, Shougang Zhuang1,2* 1 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China, 2 Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, United States of America, 3 Department of Laboratory Medicine, Shekou People’s Hospital, Shenzhen, Guangdong Providence, China Abstract Background: Recently, 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/Findings: 5/6 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 chemoat- tractant 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 Significance: These 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. Citation: Liu N, He S, Tolbert E, Gong R, Bayliss G, et al. (2012) Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney. PLoS ONE 7(4): e36194. doi:10.1371/journal.pone.0036194 Editor: Luzia Helena Carvalho, Centro de Pesquisa Rene Rachou/Fundac¸a˜o Oswaldo Cruz (Fiocruz-Minas), Brazil Received January 31, 2012; Accepted April 3, 2012; Published April 27, 2012 Copyright: 2012 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the National Institutes of Health (DK-071997, and DK-085065) and the Brown Kidney Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: szhuang@lifespan.org Introduction The pathogenesis of chronic kidney disease (CKD) in most cases involves a complex interaction of hemodynamic and inflammatory processes that leads to glomerular and vascular sclerosis and tubulointerstitial scarring with subsequent progression toward ESRD. Although therapeutic interventions such as the blockade of the rennin- angiotensin-aldosterone system and immunosuppressive drugs slow the progression of renal disease and promote renoprotective effects in experimental animal models [1,2] and in humans [3,4], these strategies cannot halt the progression of renal fibrosis and scarring. The development and progression of renal fibrosis is primarily involved in the differentiation of renal fibroblasts into myofibroblasts and infiltration of inflammatory cells, regulated by numerous cytokines and growth factors. Thus a therapeutic intervention that blocks the activation of multiple cytokine and growth factor receptors might improve antifibrotic effects and help slow progression of chronic nephropathies. Suramin, a FDA-approved drug that inhibits the interaction of multiple cytokines and growth factors with their receptors [5,6,7,8,9], may represent a novel therapeutic option for blocking fibrogenesis. This drug was Initially developed as a treatment for trypanosomiaisis and selected malignancies and metastatic diseases [5,6,7,8,9]. Recently, several studies have shown that administra- tion of suramin protects against the development of muscle and liver fibrosis in animal models [10,11]. By using a mouse model of unilateral urethral obstruction (UUO), we also demonstrated that suramin is effective in attenuating renal interstitial fibrosis [12,13]. This protective effect of suramin was further confirmed in a rat model of remnant kidney disease as indicated by preservation of renal tissue architecture, prevention of progressive renal interstitial fibrosis and improvement of renal function [12]. However, it remains unclear whether suramin is able to attenuate glomerular and vascular sclerosis as well as inflammation, in particular, macrophage infiltration in the remnant kidney. PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e36194