Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease

Garrett, Michael R.; Pezzolesi, Marcus G.; Korstanje, Ron

doi:10.1681/asn.2009080881

Cited by 27 publications

(24 citation statements)

References 59 publications

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“…Comparing these results with previous studies, recently summarized by Garrett et al, 1 we see that the homologous region of the Chr 1 locus has been mapped in a rat cross 7 and a human linkage study, 8 the Chr 4 locus has been mapped in two mouse crosses, B6 ϫ A 3 and B6 ϫ NZM, 4 and the homologous region of the Chr 15 locus has been mapped in a rat cross. 9 This concordance between loci can be used to narrow the interval and exclude genes in the region when we assume that it is the same gene underlying these loci.…”

Section: Discussionsupporting

confidence: 83%

“…Identifying the genes underlying common forms of kidney disease in humans has proven difficult, expensive, and time consuming. However, quantitative trait loci (QTL) for several complex traits, including renal phenotypes, 1 are concordant among mice, rats, and humans, suggesting that genetic findings from animal models are relevant to human disease. With respect to chronic kidney disease, QTL analysis using mice is likely to contribute new findings in the near future.…”

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confidence: 99%

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Uncovering Genes and Regulatory Pathways Related to Urinary Albumin Excretion

Hageman¹,

Leduc²,

Caputo³

et al. 2011

Journal of the American Society of Nephrology

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Identifying the genes underlying quantitative trait loci (QTL) for disease is difficult, mainly because of the low resolution of the approach and the complex genetics involved. However, recent advances in bioinformatics and the availability of genetic resources now make it possible to narrow the genetic intervals, test candidate genes, and define pathways affected by these QTL. In this study, we mapped three significant QTL and one suggestive QTL for an increased albumin-to-creatinine ratio on chromosomes (Chrs) 1, 4, 15, and 17, respectively, in a cross between the inbred MRL/MpJ and SM/J strains of mice. By combining data from several sources and by utilizing gene expression data, we identified Tlr12 as a likely candidate for the Chr 4 QTL. Through the mapping of 33,881 transcripts measured by microarray on kidney RNA from each of the 173 male F2 animals, we identified several downstream pathways associated with these QTL, including the glycan degradation, leukocyte migration, and antigen-presenting pathways. We demonstrate that by combining data from multiple sources, we can identify not only genes that are likely to be causal candidates for QTL but also the pathways through which these genes act to alter phenotypes. This combined approach provides valuable insights into the causes and consequences of renal disease. Chronic kidney disease is a growing medical problem caused by various environmental and genetic factors. Identifying the genes underlying common forms of kidney disease in humans has proven difficult, expensive, and time consuming. However, quantitative trait loci (QTL) for several complex traits, including renal phenotypes, 1 are concordant among mice, rats, and humans, suggesting that genetic findings from animal models are relevant to human disease. With respect to chronic kidney disease, QTL analysis using mice is likely to contribute new findings in the near future.In addition to mapping the causative loci, it is of equal importance to identify the pathways regulated by the loci so that we gain a better understanding of the processes that drive renal damage. One approach to identify the genes that are driven by certain loci is a method known as genetical genomics, in which gene transcripts are treated as quantitative traits and mapped in a cross in the same way as any other phenotype. 2 In this study we generated an F2 intercross between the kidney damage-susceptible SM/J (SM) and the nonsusceptible MRL/MpJ (MRL) mouse inbred strains. In addition to measuring the urinary albumin-to-creatinine ratio (ACR), we obtained a kidney expression profile from each mouse using Affymetrix arrays. This allowed us to identify the loci responsible for the difference in ACR between

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Section: Discussionsupporting

confidence: 83%

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confidence: 99%

Uncovering Genes and Regulatory Pathways Related to Urinary Albumin Excretion

Hageman¹,

Leduc²,

Caputo³

et al. 2011

Journal of the American Society of Nephrology

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“…A great deal of concordance exists for rodent and human QTL for many traits including high-density lipoprotein cholesterol, 47 kidney function, 26,48 and bone density. 49 Emerging data suggest that such is also the case for erythroid traits.…”

Section: Discussionmentioning

confidence: 99%

Sequence variation at multiple loci influences red cell hemoglobin concentration

Peters

Shavit²,

Lambert

et al. 2010

Blood

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A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci analyses to identify chromosome regions harboring genes influencing red cell hemoglobin concentration using the cell hemoglobin concentration mean (CHCM), a directly measured parameter analogous to the mean cell hemoglobin concentration. Fourteen significant loci (gene symbols Chcmq1-Chcmq14) were detected. Seven of these influenced CHCM in a sex-specific fashion, and 2 showed significant interactive effects (epistasis). For quantitative trait locus/ loci detected in multiple crosses, confidence intervals were narrowed using statistical and bioinformatic approaches. Two strong candidate genes emerged and were further analyzed: adult ␤-globin (Hbb) for

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“…2 In particular, the critical role of genetic factors in the etiology, pathogenesis, and progression of many renal disorders is gradually becoming clear, especially in children. 3 Indeed, the advent of high-throughput sequencing techniques has fostered the identification of novel causative genes and allows the continuous discovery of genetic variants of unknown clinical significance, often raising the problem of the functional testing of their pathogenic role. 4 However, emerging evidence suggests that influence of the genomic background of the patient and epigenetics are critical for determining the clinical phenotype.…”

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Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

Lazzeri¹,

Ronconi

Angelotti³

et al. 2015

Journal of the American Society of Nephrology

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The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in longterm culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders. 26: 196126: -197426: , 201526: . doi: 10.1681 The incidence of AKI and CKD is rising and reaching epidemic proportions. 1 In patients with CKD, the progressive decline in renal function is multifactorial and attributable to a variety of mechanisms. 2 In particular, the critical role of genetic factors in the etiology, pathogenesis, and progression of many renal disorders is gradually becoming clear, especially in children. 3 Indeed, the advent of high-throughput sequencing techniques has fostered the identification of novel causative genes and allows the continuous discovery of genetic variants of unknown clinical significance, often raising the problem of the functional testing of their pathogenic role. 4 However, emerging evidence suggests that influence of the J Am Soc Nephrol

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Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease

Cited by 27 publications

References 59 publications

Uncovering Genes and Regulatory Pathways Related to Urinary Albumin Excretion

Uncovering Genes and Regulatory Pathways Related to Urinary Albumin Excretion

Sequence variation at multiple loci influences red cell hemoglobin concentration

Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

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