Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4 Hassan Askari 1 , Ehsan Raeis Abdullahi 1 , Vahdat Poortahmasebi 2 , Mohammad Foad Abazari 3 , , Matin Asghari 4 , Solmaz Sadeghi 5 , Danya Abazari 6 , Reza Mahmoudi 7 , Amir Savardashtaki 8 and Mansour Poorebrahim 5* 1 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 2 Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran 3 Department of Genetics, Islamic Azad University, Tehran Medical Branch, Tehran, Iran 4 Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute of Biotechnology, ACECR, Isfahan, Iran 5 Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran 6 Department of Biology, Centre for Biomedical Research, University of Victoria, Canada 7 Department of Agricultural Biotechnology, Faculty of Agriculture, Tarbiat Modarres University, Tehran, Iran 8 Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran * Corresponding author: Mansour Poorebrahim, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran, Tel: 8(4852)460935; E-mail: mpoorebrahim@razi.tums.ac.ir Received date: Febraury 18, 2017; Accepted date: March 24, 2017; Published date: March 31, 2017 Copyright: © 2017 Askari H, 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. Abstract It is well documented that use of Cisplatin, Lead acetate and Cyclosporine in the chemotherapy and medical interventions is highly associated with nephrotoxicity and interrelated comorbidities. Here, we proposed the possible molecular mechanisms responsible for nephrotoxicity of these compounds. We utilized the microarray dataset GSE59913 consisting of approximately 600 different compounds profiled in up to 8 different tissues. After analysis with GEO2R, gene expression profiles of three aforementioned compounds were integrated with protein-protein interactions (PPI) networks and topological properties of the networks were measured using Cytoscape software. We found several key genes and signaling pathways that seem to be involved in nephrotoxicity of the examined compounds. Myc and Smad4 were identified as principal players of three compounds’ nephrotoxicity through various pathways. Our results revealed the critical functions of Il2, Jak-Stat, Mapk-Pi3k, TGFβ and Ca 2+ signaling pathways as well as novel biomarkers that may mediate the nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine. The significantly altered genes in the compound-treated samples were substantially correlated with regulation of cell proliferation, apoptosis, inflammatory responses and homeostatic processes. This study reveals the important hub genes, biological networks and key pathways as well as novel biomarkers involved in nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine. Keywords: Nephrotoxicity; Cisplatin; Lead acetate; Cyclosporine; PPI Networks Introduction Te kidney is an important organ prerequisite by the body to perform several essential regulatory roles including the maintenance of homeostasis, regulation of the extracellular environment, such as detoxifcation, and excretion of toxic metabolites and drugs [1]. Terefore, the kidney can be considered as a vital target tissue for exogenous toxicants. Nephrotoxicity is a kidney-specifc characteristic in which excretion does not go slowly owing to toxic chemicals or drugs [2,3]. Approximately 20% of nephrotoxicity in community and hospital acquired episodes is induced by drugs, among older adults, the incidence of drug-induced nephrotoxicity may rise as 66% as the average life span increases. Chemotherapy or anticancer medicine has been of limited use due to nephrotoxicity [4-7]. Cellular toxicity probably has a multifactorial etiology which is related to alterations in renal vascular cells, modifying renal hemodynamics and the relative ischemia induced by vasoconstriction potentiating sub lethal changes in renal tubular epithelial cells. Histopathological evidence of cell damage will be apparent only if the toxic injury exceeds the capacity of the cellular mechanisms to respond to the toxic insult [8]. It is widely acknowledged that patients treated with the Cyclosporine and Cisplatin are at a high risk of developing nephrotoxicity [9,10]. Studies have demonstrated that Cyclosporine causes vasoconstriction of the aferent and eferent glomerular arterioles and reductions in renal blood fow and glomerular fltration rate [11,12]. Cisplatin is an important antineoplastic drug used for the treatment of cancers. Its major dose limiting adverse efect is nephrotoxicity; 20% of patients receiving high-dose Cisplatin have intensive renal failure [10,13]. Furthermore, rat’s exposure to environmental pollutants such as Lead acetate induced nephrotoxicity [14]. However, the mechanism behind these Compounds remains a matter of debate. Since nephrotoxicity largely afects human health and has a poorly understood pathogenesis, several studies have examined this condition. Moreover, the spectrum of temporal pathway deregulation has not been studied using integrative framework. Bearing this fact in mind, understanding the toxic mechanisms for nephrotoxicity renders advantageous information on the development of drugs with both potential therapeutic benefts and reduced adverse efects. To this end, analysis of PPI and gene regulatory networks (GRNs) has emerged as a promising tool and can help to decipher in-depth biological aspects of Askari et al., Biol Syst Open Access 2017, 6:1 DOI: 10.4172/2329-6577.1000176 Research Article Open Access Biol Syst Open Access, an open access journal ISSN:2329-6577 Volume 6 • Issue 1 • 1000176 B i o l o g i c a l S y s t e m s : O p e n A c c e s s ISSN: 2329-6577 Biological Systems: Open Access