Dataset Information

Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach.

ABSTRACT: Chronic allograft damage, defined by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of allograft failure. Few effective therapeutic options are available to prevent the progression of IF/TA. We applied a meta-analysis approach on IF/TA molecular datasets in Gene Expression Omnibus to identify a robust 85-gene signature, which was used for computational drug repurposing analysis. Among the top ranked compounds predicted to be therapeutic for IF/TA were azathioprine, a drug to prevent acute rejection in renal transplantation, and kaempferol and esculetin, two drugs not previously described to have efficacy for IF/TA. We experimentally validated the anti-fibrosis effects of kaempferol and esculetin using renal tubular cells in vitro and in vivo in a mouse Unilateral Ureteric Obstruction (UUO) model. Kaempferol significantly attenuated TGF-?1-mediated profibrotic pathways in vitro and in vivo, while esculetin significantly inhibited Wnt/?-catenin pathway in vitro and in vivo. Histology confirmed significantly abrogated fibrosis by kaempferol and esculetin in vivo. We developed an integrative computational framework to identify kaempferol and esculetin as putatively novel therapies for IF/TA and provided experimental evidence for their therapeutic activities in vitro and in vivo using preclinical models. The findings suggest that both drugs might serve as therapeutic options for IF/TA.

SUBMITTER: Li L

PROVIDER: S-EPMC5209709 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach.

Li Li L Greene Ilana I Readhead Benjamin B Menon Madhav C MC Kidd Brian A BA Uzilov Andrew V AV Wei Chengguo C Philippe Nimrod N Schroppel Bernd B He John Cijiang JC Chen Rong R Dudley Joel T JT Murphy Barbara B

Scientific reports 20170104

Chronic allograft damage, defined by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of allograft failure. Few effective therapeutic options are available to prevent the progression of IF/TA. We applied a meta-analysis approach on IF/TA molecular datasets in Gene Expression Omnibus to identify a robust 85-gene signature, which was used for computational drug repurposing analysis. Among the top ranked compounds predicted to be therapeutic for IF/TA were azathioprine, a drug ...[more]

PMID: 28051114

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Project description:BACKGROUND Interstitial fibrosis and tubular atrophy (IF/TA) have been recognized as crucial factors contributing to graft loss resulting from chronic renal allograft injuries. Recent studies have indicated a significant association between the progression of organ fibrosis and single nucleotide polymorphisms (SNPs) found on certain genes. Our research sought to understand these potential associations and detect the potential impact of SNPs on ubiquitin-related genes related to allograft fibrosis in kidney transplant recipients. MATERIAL AND METHODS There were 200 patients enrolled in this study, from which samples were extracted for total DNA. Targeted next-generation sequencing was used to detect SNPs on 9 genes (FBXL21, PIAS1/2, SUMO1/2/3/4, UBE2D1, and UBE2I). Minor allele frequency (MAF) and Hardy-Weinberg equilibrium (HWE) tests were used and followed by linkage disequilibrium analysis. General linear models (GLM) were used to identify significant confounding factors. Finally, multiple inheritance models and haplotype analyses were conducted to explore associations between SNPs and the degree of the severity of renal allograft fibrosis. RESULTS In total, 144 SNPs were identified in targeted sequencing. After filtering based on results from MAF and HWE tests, 15 tagger SNPs were selected for further analyses of associations. GLMs indicated that the administration of sirolimus significantly contributed to the degree of severity of allograft fibrosis (P=0.011). After adjusting for confounding factors and applying a Bonferroni correction, multiple inheritance model analyses indicated that the recessive model of rs644731 of the PIAS2 gene was significantly correlated with the occurrence of IF/TA (P=0.01). Furthermore, single-locus based analysis of rs644731 did not indicate that it had a positive influence on IF/TA in a degree-dependent manner. Finally, linkage disequilibrium analysis revealed 3 haplotypes all lacking significant correlation with respect to the IF/TA experimental cohort. CONCLUSIONS We are the first to reveal that mutations of rs644731 in the PIAS2 gene were significantly correlated with the progression of IF/TA in kidney transplant recipients.

Project description:Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a "hub" protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of monitoring these urinary proteins for the specific and sensitive noninvasive diagnosis of acute renal allograft rejection.

Dataset Information

Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach.

Publications

Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach.

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