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A kidney-specific genome-scale metabolic network model for analyzing focal segmental glomerulosclerosis

Author:
Sohrabi-Jahromi, Salma, Marashi, Sayed-Amir, Kalantari, Shiva
Source:
Mammalian genome 2016 v.27 no.3-4 pp. 158-167
ISSN:
0938-8990
Subject:
adults, amino acid metabolism, biomarkers, biosynthesis, children, chondroitin sulfate, disease models, drugs, genes, kidneys, nephrotic syndrome, pathogenesis, patients, proteome, pyridoxine, renal failure, sulfates, transcriptome
Abstract:
Focal Segmental Glomerulosclerosis (FSGS) is a type of nephrotic syndrome which accounts for 20 and 40 % of such cases in children and adults, respectively. The high prevalence of FSGS makes it the most common primary glomerular disorder causing end-stage renal disease. Although the pathogenesis of this disorder has been widely investigated, the exact mechanism underlying this disease is still to be discovered. Current therapies seek to stop the progression of FSGS and often fail to cure the patients since progression to end-stage renal failure is usually inevitable. In the present work, we use a kidney-specific metabolic network model to study FSGS. The model was obtained by merging two previously published kidney-specific metabolic network models. The validity of the new model was checked by comparing the inactivating reaction genes identified in silico to the list of kidney disease implicated genes. To model the disease state, we used a complete list of FSGS metabolic biomarkers extracted from transcriptome and proteome profiling of patients as well as genetic deficiencies known to cause FSGS. We observed that some specific pathways including chondroitin sulfate degradation, eicosanoid metabolism, keratan sulfate biosynthesis, vitamin B6 metabolism, and amino acid metabolism tend to show variations in FSGS model compared to healthy kidney. Furthermore, we computationally searched for the potential drug targets that can revert the diseased metabolic state to the healthy state. Interestingly, only one drug target, N-acetylgalactosaminidase, was found whose inhibition could alter cellular metabolism towards healthy state.
Agid:
5177437