Systems biology of kidney diseases
ABSTRACT Kidney diseases manifest in progressive loss of renal function, which ultimately leads to complete kidney failure. The mechanisms underlying the origins and progression of kidney diseases are not fully understood. Multiple factors involved in the pathogenesis of kidney diseases have made the traditional candidate gene approach of limited value toward full understanding of the molecular mechanisms of these diseases. A systems biology approach that integrates computational modeling with large-scale data gathering of the molecular changes could be useful in identifying the multiple interacting genes and their products that drive kidney diseases. Advances in biotechnology now make it possible to gather large data sets to characterize the role of the genome, epigenome, transcriptome, proteome, and metabolome in kidney diseases. When combined with computational analyses, these experimental approaches will provide a comprehensive understanding of the underlying biological processes. Multiscale analysis that connects the molecular interactions and cell biology of different kidney cells to renal physiology and pathology can be utilized to identify modules of biological and clinical importance that are perturbed in disease processes. This integration of experimental approaches and computational modeling is expected to generate new knowledge that can help to identify marker sets to guide the diagnosis, monitor disease progression, and identify new therapeutic targets.
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- "Traditionally, diagnostic and treatment decisions in kidney disease have been based on kidney histology, biochemical marker analysis , and clinical manifestations. Recently, systems biology has been found valuable for studying the origin of kidney disease, predicting disease progression, and recognizing early biomarkers (He et al., 2012). Therefore, to obtain more information on the effect of hyperuricemia on the kidney, we analyzed global changes in the urine metabolome and evaluated the pathophysiological outcome in the mouse kidney. "
ABSTRACT: Clinical studies show that hyperuricemia is a risk factor in the progression and development of cardiovascular and metabolic disease. Elevated serum levels of uric acid induce renal injury via an inflammation response, but the detailed mechanism is still under study. To better understand the effect of hyperuricemia on the kidney, we used gas chromatography-mass spectrometry-based metabolomics to investigate the role of uric acid in the mouse kidney. Partial least-squares discriminant analysis revealed significant differences between control and hyperuricemia groups in urine metabolic profiles. We identified 33 metabolites from 76 highly reproducible peaks and found abnormal uric acid levels related to comprehensive kidney injury, including excretive function and energy metabolism. Additionally, inflammation induced by the interleukin 6/signal transducer and activator of transcription 3 signaling pathway participated in hyperuricemia-induced kidney injury. This study helps understand the relationship between hyperuricemia and kidney injury. Metabolomics may be a useful strategy for early diagnosis of kidney damage.Food and Chemical Toxicology 09/2014; 74. DOI:10.1016/j.fct.2014.08.017 · 2.90 Impact Factor
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- "Mechanistic basis for overcoming platinum resistance using copper chelating agents. Mol Cancer Ther 2012; 11: 2483–2494. 105. "
ABSTRACT: The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.Cell Death & Disease 05/2014; 5(5):e1257. DOI:10.1038/cddis.2013.428 · 5.18 Impact Factor
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- "34.9% of urinary proteins are also present in plasma and penetrate into the urine through glomerular filtration. The remaining 65.1% (up to 2000 proteins) of the urinary proteome are secreted by epithelial cells of the kidney and urogenital system or added to the urine by means of cell death or secretion of exosomes . "
ABSTRACT: The urine protein composition samples of ten Russian cosmonauts (male, aged of 35 up to 51) performed long flight missions and varied from 169 up to 199 days on the International Space Station (ISS) were analyzed. As a control group, urine samples of six back-up cosmonauts were analyzed. We used proteomic techniques to obtain data and contemporary bioinformatics approaches to perform the analysis. From the total number of identified proteins (238) in our data set, 129 were associated with a known tissue origin. Preflight samples contained 92 tissue-specific proteins, samples obtained on Day 1 after landing had 90 such proteins, while Day 7 samples offered 95 tissue-specific proteins. Analysis showed that consistently present proteins in urine (under physiological conditions and after space flight) are cubilin, epidermal growth factor, kallikrein-1, kininogen-1, megalin, osteopontin, vitamin K-dependent protein Z, uromodulin. Variably present proteins consists of: Na(+)/K(+) ATPase subunit gamma, β-defensin-1, dipeptidyl peptidase 4, maltasa-glucoamilasa, cadherin-like protein, neutral endopeptidase and vascular cell adhesion protein 1. And only three renal proteins were related to the space flight factors. They were not found in the pre-flight samples and in the back-up cosmonaut urine, but were found in the urine samples after space flight: AFAM (afamin), AMPE (aminopeptidase A) and AQP2 (aquaporin-2). This data related with physiological readaptation of water-salt balance. The proteomic analysis of urine samples in different phases of space missions with bioinformation approach to protein identification provides new data relative to biomechemical mechanism of kidney functioning after space flight.PLoS ONE 08/2013; 8(8):e71652. DOI:10.1371/journal.pone.0071652 · 3.23 Impact Factor