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Yoram Yagil

Publications and source records attributed to Yoram Yagil.

At least 19 recordsLinked to original sources
PubMed2007

Metabolic and genomic dissection of diabetes in the Cohen rat.

We investigated the metabolic and genetic basis of diabetes in the Cohen Diabetic rat, a model of diet-induced diabetes, as a means to identify the molecular mechanisms involved. By altering individual components in the diabetogenic diet, we established that the dietary susceptibility that leads to the development of diabetes in this model is directly related to the high casein and low copper content in chow. The development of diabetes is accompanied by depletion of the acini from the exocrine pancreas and replacement with fat cells, while the appearance of the islets of Langerhans remains intact. With reversion back from diabetogenic to regular diet, the diabetic phenotype disappears but the histological changes in the exocrine pancreas prevail. Using positional cloning, we detected a major quantitative trait locus (QTL) on rat chromosome 4 with a chromosomal span of 4.9 cM, and two additional loci on chromosomes 7 and X. A screen for genes within that QTL in the rat and in the syntenic regions in mouse and man revealed only 23 candidate genes. Notable among these genes is Ica1, which has been causally associated with diabetes and bovine casein. We conclude that the development of diabetes in our model is dependent upon high casein and low copper in diet, that it is accompanied by histomorphological changes in the exocrine but not endocrine pancreas, that it is reversible, and that it is associated with a major QTL on chromosome 4 in which we detected Ica1, a high priority candidate gene.

Analysis of Variance↗
PubMed2006

Genetic dissection of proteinuria in the Sabra rat.

The pathophysiology underlying proteinuria remains incompletely understood and warrants further research. We currently initiated the investigation of the genetic basis of proteinuria in the Sabra rat, a model of salt susceptibility that we showed previously to be also a model of spontaneous proteinuria that is unrelated to salt loading or development of hypertension. We applied the total genome scan strategy in 75 F2 male animals derived from a cross between SBH/y, which are prone to develop proteinuria, and SBN/y, which are relatively resistant to the development of proteinuria. Animals were subjected to uninephrectomy (UNx) to accelerate the development of proteinuria and were provided chow with a low salt content, thus avoiding the development of hypertension. Urinary protein excretion was monitored before UNx and monthly thereafter for 8 mo. The genotype of F2 was determined with microsatellite markers. The data were analyzed for cosegregation by ANOVA and for genetic linkage with a novel multifaceted statistical genetic paradigm. We detected three proteinuria-related quantitative trait loci (QTL) that were associated with the salt sensitivity (H) alleles from SBH/y: SUP2, SUP17, and SUP20 on rat chromosomes (Chr) 2, 17, and 20. We detected an additional QTL on Chr 3, SUP3, that was associated with the salt resistance (N) alleles from SBN/y. A temporal effect was noted: QTL SUP2 and SUP17 surfaced at months 7-8, QTL SUP20 at months 6-8, and QTL SUP3 at months 5-6. The QTL emerging from this study lead us a step closer to identifying the genes associated with and elucidating the pathophysiology of proteinuria.

Animals↗
PubMed2006

Integration--a key to success in the genetic dissection of complex diseases?

Complex diseases are polygenic and multifactorial. The outcome of two decades of search for the culprit genes in complex diseases involving the cardiovascular system has been less than satisfactory. Genomic studies using linkage analysis have led so far to the detection of a large number of quantitative trait loci that embed a large number of candidate genes. Transcriptomic studies using differential gene expression profiling and DNA microarrays have also generated hundreds of potential candidate genes. None of these genetic strategies has enabled researchers to reduce the number of genes to a manageable number or to identify the specific culprit genes. We recently proposed that the search for genes involved in complex diseases such as hypertension might benefit from an integration of genomics and transcriptomics as a logical alternative strategy to using either approach alone. We applied this integrated genomic-transcriptomic approach to identify the genes that are involved in the pathogenesis of hypertension in the Sabra rat model of salt susceptibility. We successfully identified seven novel candidate genes for hypertension, an outcome that could not have been achieved by genomics or transcriptomics alone.

Animals↗
PubMed2005

Novel integrative approaches to the identification of candidate genes in hypertension.

Hypertension, diabetes, and obesity are common diseases that are genetically expressed as complex traits. The clinical expression of these diseases, which run in families but have no clear pattern of inheritance, has been attributed to the interaction between multiple genes and the environment. Identifying the underlying genes, a crucial step in understanding the molecular pathogenesis of complex diseases, has had limited success so far, stressing the need for novel strategies to move this process forward. Innovative integrative genetic-genomic approaches have been proposed recently for the identification of new high-priority candidate genes. These strategies, which combine expression profiling with genetic linkage in different ways, may represent a breakthrough in the search for the genes involved in complex diseases.

Animals↗
PubMed2005

Identification of hypertension-related genes through an integrated genomic-transcriptomic approach.

In search for the genetic basis of hypertension, we applied an integrated genomic-transcriptomic approach to identify genes involved in the pathogenesis of hypertension in the Sabra rat model of salt-susceptibility. In the genomic arm of the project, we previously detected in male rats two salt-susceptibility QTLs on chromosome 1, SS1a (D1Mgh2-D1Mit11; span 43.1 cM) and SS1b (D1Mit11-D1Mit4; span 18 cM). In the transcriptomic arm, we studied differential gene expression in kidneys of SBH/y and SBN/y rats that had been fed regular diet or salt-loaded. We used the Affymetrix Rat Genome RAE230 GeneChip and probed >30,000 transcripts. The research algorithm called for an initial genome-wide screen for differentially expressed transcripts between the study groups. This step was followed by cluster analysis based on 2x2 ANOVA to identify transcripts that were of relevance specifically to salt-sensitivity and hypertension and to salt-resistance. The two arms of the project were integrated by identifying those differentially expressed transcripts that showed an allele-specific hypertensive effect on salt-loading and that mapped within the defined boundaries of the salt-susceptibility QTLs on chromosome 1. The differentially expressed transcripts were confirmed by RT-PCR. Of the 2933 genes annotated to rat chromosome 1, 1102 genes were identified within the boundaries of the two blood pressure QTLs. The microarray identified 2470 transcripts that were differentially expressed between the study groups. Cluster analysis identified genome-wide 192 genes that were relevant to salt-susceptibility and/or hypertension, 19 of which mapped to chromosome 1. Eight of these genes mapped within the boundaries of QTLs SS1a and SS1b. RT-PCR confirmed 7 genes, leaving TcTex1, Myadm, Lisch7, Axl-like, Fah, PRC1-like, and Serpinh1. None of these genes has been implicated in hypertension before. These genes become henceforth targets for our continuing search for the genetic basis of hypertension.

Algorithms↗
PubMed2005

The search for the genetic basis of hypertension.

PURPOSE OF REVIEW: This review surveys the literature on the search for the genetic basis of hypertension during the 10 months since November 2003. The goals set forth by this search are defined and the highlights of the work accomplished are provided. RECENT FINDINGS: The search for the genetic basis of hypertension is ongoing, generating an abundance of new data. These data consist of a large number of candidate genes, association of previously known and novel candidate genes with various facets of hypertension, detection of new quantitative trait loci and identification of genes that mediate susceptibility to hypertension. The renin-zangiotensin-aldosterone system continues to dominate the interest of investigators. Other gene systems are also emerging but a single-gene system cannot be singled out beyond the renin-angiotensin-aldosterone system and the data are mostly sporadic and do not reflect a guided or coordinated effort to resolve unanswered issues. The notion that hypertension is polygenic is reinforced, yet few data are provided as to the actual number of genes involved, gene-gene interaction or gene-environment interaction. Advanced biotechnological tools involving transcriptomics and proteomics are underused. SUMMARY: Research on the genetic basis of hypertension has generated over the past year a large number of candidate genes and tied them to various aspects of hypertension. How these genes fit into the complex pathophysiological network that induces hypertension remains unclear. The task of putting together these genes into a cohesive framework still lies ahead, but promises to enlighten us as to the true nature of hypertension, the pathogenic mechanisms involved and improved therapeutic and preventive measures.

Biomedical Research↗
PubMed2005

Nonproteinuric diabetes-associated nephropathy in the Cohen rat model of type 2 diabetes.

The Cohen diabetic rat is an experimental model reminiscent of human type 2 diabetes. The aim of this study was to characterize the development of end-organ damage in this model. Cohen diabetic sensitive (CDs) and Cohen diabetic resistant (CDr) rats were fed regular diet or a diabetogenic diet. Glucose tolerance, renal function, and renal and retinal histology were studied at set intervals. CDs fed diabetogenic diet were the only strain that expressed the diabetic metabolic phenotype. In this strain, urinary protein excretion did not increase with the development of diabetes, but plasma urea and creatinine levels increased and creatinine clearance decreased. Light microscopy revealed in CDs enlarged glomeruli with increased mesangial matrix and thickening of the glomerular capillary wall; electron microscopy demonstrated thickened basement membrane and mesangial abundance. There was increased staining for type IV collagen in glomeruli and interstitium of CDs. The retinas of diabetic CDs demonstrated pathology consistent with nonproliferative diabetic retinopathy. The histological findings in the kidneys, the absence of proteinuria, the impairment in glomerular filtration, and the development of retinopathy in CDs are consistent with diabetes-associated nephropathy that is similar to a nonalbuminuric type of nephropathy associated with type 2 diabetes in humans.

Animals↗
PubMed2005

Hemodynamic effects of anemia correction by recombinant human erythropoietin in predialysis patients with renal failure.

Most patients with chronic renal failure have anemia, which can be corrected by recombinant human erythropoietin (rHuEpo) treatment. Increase in arterial pressure (AP) was reported in some studies and was related to higher systemic vascular resistance induced either by the rise of erythrocyte mass or the change in various endogenous vasopressors, including the direct action of rHuEpo itself. We investigated the effect of rHuEpo treatment on hemodynamic variables, including small and large arterial compliance in 20 patients with chronic renal failure who were not receiving dialysis (CCT 29 +/- 12 mL/min), with Hb levels of 40.4 +/- 0.58 g/dL. They were treated with 2,000 units intravenously followed by 80 to 120 s/c units/kg/body weight, with dosage titration according to Hb level. Noninvasive hemodynamic evaluation was performed before the first rHuEpo treatment, 30 min after the first IV rHuEpo administration and at least 3 months later when target hemoglobin (Hb) and hematocrit (Hct) were reached. No rise in AP occurred after rHuEpo administration either short term or long term. The significant hemodynamic changes were a fall in pulse pressure and a rise in large artery compliance, with no change in small artery compliance after 3 months of rHuEpo treatment when Hb and Hct levels were corrected. These findings show improvement in arterial stiffness when Hb is corrected with rHuEpo treatment.

Aged↗
PubMed2004

Primed polymorphonuclear leukocytes, oxidative stress, and inflammation antecede hypertension in the Sabra rat.

Hypertension is accompanied by systemic oxidative stress, inflammation, and priming of peripheral polymorphonuclear leukocytes (PMNLs), yet the involvement of these factors in the pathophysiology of hypertension is incompletely understood. We investigated the relationship between oxidative stress, primed PMNLs, and inflammation and the development of hypertension in the Sabra rat model of salt-sensitive hypertension. Sabra hypertension-resistant rats (SBN/y) (salt-resistant) and Sabra hypertension-prone rats (SBH/y) (salt-sensitive) were studied under normal conditions or during salt loading. Systolic blood pressure (BP) was measured by the tail-cuff method. The extent of oxidative stress was evaluated by the rate of superoxide release from PMNLs, plasma-reduced glutathione (GSH) levels, malondialdehyde (MDA) levels (estimated by thiobarbituric acid-reacting substances), and plasma-carbonylated fibrinogen (Western blotting). Plasma fibrinogen levels and the peripheral PMNL count served as indices of inflammation. In SBH/y and SBN/y provided regular chow without salt loading, BP did not rise above baseline values, yet superoxide release, plasma MDA, carbonylated fibrinogen, and PMNL count were higher in SBH/y than in SBN/y, whereas GSH levels were lower in SBH/y. Four weeks of salt loading resulted in a gradual increase in systolic BP in SBH/y to 205+/-3 mm Hg, whereas BP remained in SBN/y at baseline normotensive levels. All the parameters reflecting oxidative stress and inflammation were further aggravated with the development of hypertension in salt-loaded SBH/y. We conclude that primed PMNLs, oxidative stress, and inflammation antecede the development of hypertension in this experimental model of hypertension.

Animals↗
PubMed2003

Nephroprotective effects of the endothelin ET(A) receptor antagonist darusentan in salt-sensitive genetic hypertension.

We tested the effect of selective endothelin ET(A) receptor blockade on the development renal damage in the Sabra rat model of genetic salt-sensitivity. Animals from the salt-sensitive (SBH/y) and salt-resistant strains (SBN/y) were either salt-loaded with deoxycorticosterone acetate and salt (DOCA) or fed a normal diet. Additional salt-loaded groups were also treated with the selective ET(A) antagonist darusentan (DA). Salt-loading in SBH/y increased systolic blood pressure by 75 mm Hg and urinary albumin excretion 23-fold (P<0.0001). Darusentan attenuated the rise of systolic blood pressure (50%) and urinary albumin excretion (63%, P<0.01, respectively). Salt-loading in SBH/y was associated with significant increased osteopontin mRNA expression as well as glomerulosclerosis and tubulointerstitial damage in the kidney (P<0.05, respectively). This was either significantly reduced or normalized by darusentan (P<0.05, respectively). Thus, darusentan confers a significant renal protection in the Sabra model of salt-sensitive hypertension.

Albuminuria↗
PubMed2003

Congenic strains confirm the presence of salt-sensitivity QTLs on chromosome 1 in the Sabra rat model of hypertension.

We previously detected by linkage analysis in segregating populations derived from crosses between the Sabra hypertension-prone rat (SBH/y) and the hypertension-resistant strain (SBN/y) two QTLs for salt susceptibility on chromosome 1, with sex specificity: in males SS1a and SS1b, and in females SS1b only. To provide support for a functional role of these QTLs in relation to hypertension, we constructed congenic strains by replacing most of or selected segments from chromosome 1 from SBN/y with the homologous chromosomal regions of SBH/y, or reciprocally from SBH/y with segments of SBN/y, leaving the other chromosomes unperturbed. Genetic screening with over 150 microsatellite markers confirmed the homozygosity of the targeted genomic inserts and of the remainder of the genomic background. The phenotype of the congenic strains was tested by salt loading with DOCA-salt over a 4-wk period and measuring blood pressure by tail-cuff (in all animals) or radiotelemetry (in select groups) at baseline and during salt loading. In the congenic strains in which a chromosomal segment incorporating QTL SS1a from SBN/y was introgressed onto the genomic background of SBH/y, the blood pressure response to salt loading, as measured by tail-cuff, was decreased by 16 mmHg in both males and females compared with the parental SBH/y; replacing the QTL SS1b reduced the blood pressure response by 30 and 21 mmHg, respectively. In the congenic strains in which both SS1a and SS1b were introgressed from SBN/y onto the genomic background of SBH/y, the reduction in blood pressure was 34 mmHg in males and 38 mmHg in females; these latter results were confirmed by radiotelemetry. When either one or both QTLs together were introgressed from SBH/y onto the SBN/y genomic background, tail-cuff measurements failed to detect an increase in blood pressure above baseline; telemetric measurements in the congenic strains introgressing both QTLs together, however, detected a significant rise in blood pressure after 3 and 4 wk of salt loading. Neither the origin of the Y chromosome nor the sex of the parental strain had any significant impact on the magnitude of the blood pressure response to salt loading. We conclude that the congenic rat strains that we constructed for the chromosome 1 QTLs provide functional evidence for the role of gene systems within QTLs SS1a and SS1b in the blood pressure response to salt loading. The unexpected finding was that QTL SS1a contributes to the hypertensive response also in females. The data indicate the lack of a Y chromosomal effect or of parental imprinting.

Animals↗