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Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes.

Grigoryev DN, Cheranova DI, Heruth DP, Huang P, Zhang LQ, Rabb H, Ye SQ - BMC Nephrol (2013)

Bottom Line: The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach.Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri School of Medicine, Kansas City, MO, USA. dgrigoryev@cmh.edu.

ABSTRACT

Background: Accumulated to-date microarray data on ischemia reperfusion injury (IRI) of kidney represent a powerful source for identifying new targets and mechanisms of kidney IRI. In this study, we conducted a meta-analysis of gene expression profiles of kidney IRI in human, pig, rat, and mouse models, using a new scoring method to correct for the bias of overrepresented species. The gene expression profiles were obtained from the public repositories for 24 different models. After filtering against inclusion criteria 21 experimental settings were selected for meta-analysis and were represented by 11 rat models, 6 mouse models, and 2 models each for pig and human, with a total of 150 samples. Meta-analysis was conducted using expression-based genome-wide association study (eGWAS). The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.

Results: Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach. Pathway analysis of our candidates identified "Acute renal failure panel" as the most implicated pathway, which further validates our new method. Among new IRI candidates were 10 novel (<5 published reports related to kidney IRI) and 11 new candidates (0 reports related to kidney IRI) including the most prominent candidates ANXA2, CLDN4, and TYROBP. The cross-species expression pattern of these genes allowed us to generate three workable hypotheses of kidney IRI, one of which was confirmed by an additional study.

Conclusions: Our first in the field kidney IRI meta-analysis of 150 microarray samples, corrected for a species bias, identified 10 novel and 11 new candidate genes. Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

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IRI-induced expression pattern of novel IRI candidate genes CLDNs and TYROBP. Panel A. The expression profiles (Y axis) of CLDN3 and CLDN4 are presented according to the tested time points (X axis). Fold changes (black bars) for each species (labeled on the bottom) are expressed in log10 values. The location of each claudin in the distal nephron is depicted in Panel B (each number corresponds to claudin nomenclature). Panel B. Diagram of nephron. Panel C. The pixilated expression values of TYROBP and CD160 genes in cortex and medulla of kidney is represented by horizontal bars. The error bars are standard deviations among 3 samples.
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Figure 4: IRI-induced expression pattern of novel IRI candidate genes CLDNs and TYROBP. Panel A. The expression profiles (Y axis) of CLDN3 and CLDN4 are presented according to the tested time points (X axis). Fold changes (black bars) for each species (labeled on the bottom) are expressed in log10 values. The location of each claudin in the distal nephron is depicted in Panel B (each number corresponds to claudin nomenclature). Panel B. Diagram of nephron. Panel C. The pixilated expression values of TYROBP and CD160 genes in cortex and medulla of kidney is represented by horizontal bars. The error bars are standard deviations among 3 samples.

Mentions: Our next candidate CLDN4 was from the claudin family. This family has the same basic function of maintaining epithelial barrier integrity and controlling paracellular transport via regulation of tight junctions between neighboring cells. Claudins are highly conserved throughout evolution and are located in close proximity in the human genome [7]. Our candidate CLDN4 is located within 50 kb of CLDN3 on chromosome 7. Furthermore, the CLDN3/CLDN4 tandem demonstrates a coordinate expression in several normal and neoplastic tissues [8]. This was concordant with our data (Figure 4A). Although CLDN3 did not satisfy Bonferroni threshold, it was ranked by our W-scoring algorithm higher (rank 22) than CLDN4 (rank 78) (Additional file 2). Moreover, the overall trend in its expression pattern was close to that of CLDN4 (Figure 4A). The slight differences in expression of the tandem CLDN3/CLDN4 members might be attributed to the additional cortex location of CLDN3 where expression pattern of CLDN3 might differ (Figure 4B).


Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes.

Grigoryev DN, Cheranova DI, Heruth DP, Huang P, Zhang LQ, Rabb H, Ye SQ - BMC Nephrol (2013)

IRI-induced expression pattern of novel IRI candidate genes CLDNs and TYROBP. Panel A. The expression profiles (Y axis) of CLDN3 and CLDN4 are presented according to the tested time points (X axis). Fold changes (black bars) for each species (labeled on the bottom) are expressed in log10 values. The location of each claudin in the distal nephron is depicted in Panel B (each number corresponds to claudin nomenclature). Panel B. Diagram of nephron. Panel C. The pixilated expression values of TYROBP and CD160 genes in cortex and medulla of kidney is represented by horizontal bars. The error bars are standard deviations among 3 samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016589&req=5

Figure 4: IRI-induced expression pattern of novel IRI candidate genes CLDNs and TYROBP. Panel A. The expression profiles (Y axis) of CLDN3 and CLDN4 are presented according to the tested time points (X axis). Fold changes (black bars) for each species (labeled on the bottom) are expressed in log10 values. The location of each claudin in the distal nephron is depicted in Panel B (each number corresponds to claudin nomenclature). Panel B. Diagram of nephron. Panel C. The pixilated expression values of TYROBP and CD160 genes in cortex and medulla of kidney is represented by horizontal bars. The error bars are standard deviations among 3 samples.
Mentions: Our next candidate CLDN4 was from the claudin family. This family has the same basic function of maintaining epithelial barrier integrity and controlling paracellular transport via regulation of tight junctions between neighboring cells. Claudins are highly conserved throughout evolution and are located in close proximity in the human genome [7]. Our candidate CLDN4 is located within 50 kb of CLDN3 on chromosome 7. Furthermore, the CLDN3/CLDN4 tandem demonstrates a coordinate expression in several normal and neoplastic tissues [8]. This was concordant with our data (Figure 4A). Although CLDN3 did not satisfy Bonferroni threshold, it was ranked by our W-scoring algorithm higher (rank 22) than CLDN4 (rank 78) (Additional file 2). Moreover, the overall trend in its expression pattern was close to that of CLDN4 (Figure 4A). The slight differences in expression of the tandem CLDN3/CLDN4 members might be attributed to the additional cortex location of CLDN3 where expression pattern of CLDN3 might differ (Figure 4B).

Bottom Line: The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach.Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri School of Medicine, Kansas City, MO, USA. dgrigoryev@cmh.edu.

ABSTRACT

Background: Accumulated to-date microarray data on ischemia reperfusion injury (IRI) of kidney represent a powerful source for identifying new targets and mechanisms of kidney IRI. In this study, we conducted a meta-analysis of gene expression profiles of kidney IRI in human, pig, rat, and mouse models, using a new scoring method to correct for the bias of overrepresented species. The gene expression profiles were obtained from the public repositories for 24 different models. After filtering against inclusion criteria 21 experimental settings were selected for meta-analysis and were represented by 11 rat models, 6 mouse models, and 2 models each for pig and human, with a total of 150 samples. Meta-analysis was conducted using expression-based genome-wide association study (eGWAS). The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.

Results: Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach. Pathway analysis of our candidates identified "Acute renal failure panel" as the most implicated pathway, which further validates our new method. Among new IRI candidates were 10 novel (<5 published reports related to kidney IRI) and 11 new candidates (0 reports related to kidney IRI) including the most prominent candidates ANXA2, CLDN4, and TYROBP. The cross-species expression pattern of these genes allowed us to generate three workable hypotheses of kidney IRI, one of which was confirmed by an additional study.

Conclusions: Our first in the field kidney IRI meta-analysis of 150 microarray samples, corrected for a species bias, identified 10 novel and 11 new candidate genes. Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

Show MeSH
Related in: MedlinePlus