RESUMEN
Spontaneously hypertensive rats (SHR) display several features of the human insulin-resistance syndromes. Cd36 deficiency is genetically linked to insulin resistance in SHR. We show that transgenic expression of Cd36 in SHR ameliorates insulin resistance and lowers serum fatty acids. Our results provide direct evidence that Cd36 deficiency can promote defective insulin action and disordered fatty-acid metabolism in spontaneous hypertension.
Asunto(s)
Antígenos CD36/genética , Hipertensión/genética , Resistencia a la Insulina/genética , Animales , Animales Modificados Genéticamente , Antígenos CD36/biosíntesis , Ácidos Grasos/sangre , Prueba de Tolerancia a la Glucosa , Ratas , Ratas Endogámicas SHRRESUMEN
To investigate whether a BP-regulatory locus exists in the vicinity of the renin locus on rat chromosome 13, we transferred this chromosome segment from the Dahl salt-sensitive (S) rat onto the genetic background of the Dahl salt-resistant (R) rat. In congenic Dahl R rats carrying the S renin gene and fed an 8% salt diet, systolic BP was significantly lower than in progenitor Dahl R rats: 127 +/- 1 mmHg versus 138 +/- 4 mmHg, respectively (P < 0.05). Moreover, the decreased BP in the congenic Dahl R strain was associated with decreased kidney renin mRNA and decreased plasma renin concentration. These findings demonstrate that the Dahl S strain carries alleles in or near the renin locus that confer lower plasma renin concentration and lower BP than the corresponding alleles in the Dahl R strain, at least when studied on the genetic background of the Dahl R rat and in the environment of a high salt diet. The occurrence of coincident reductions in kidney renin mRNA, plasma renin concentration, and BP after interstrain transfer of naturally occurring renin gene variants strongly suggests that genetically determined variation in renin gene expression can affect BP.
Asunto(s)
Hipertensión/genética , Renina/genética , Alelos , Animales , Mapeo Cromosómico , Dieta , Femenino , Regulación Enzimológica de la Expresión Génica , Marcadores Genéticos , Riñón/enzimología , Masculino , ARN Mensajero/genética , Ratas , Ratas Endogámicas , Ratas Mutantes , Renina/administración & dosificación , Cloruro de Sodio DietéticoRESUMEN
The Dahl salt-sensitive rat (SS/Jr) is a widely used animal model of salt-sensitive hypertension. SS/Jr rats are believed to be highly inbred and uniformly sensitive to the hypertensinogenic effects of sodium chloride, but we have recently observed that SS/Jr rats from Harlan Sprague Dawley, Inc, exhibit considerable variability in their blood pressure response to supplemental dietary salt. To test the possibility that commercially available SS/Jr rats are genetically contaminated and therefore no longer fully inbred, we performed molecular genetic studies and blood pressure measurements in several groups of SS/Jr rats purchased from Harlan Sprague Dawley. We found molecular evidence of heterozygosity and/or atypical allelic variants involving loci on at least five different chromosomes. Many of the rats also failed to exhibit a salt-sensitive blood pressure phenotype. We conclude that SS/Jr rats being sold by the only commercial vendor of Dahl rats in the United States are genetically contaminated and resistant to the hypertensinogenic effects of salt. These findings raise serious questions about the interpretation of research conducted with SS/Jr rats obtained from Harlan Sprague Dawley.
Asunto(s)
ADN Satélite/análisis , Hipertensión/genética , Ratas Mutantes/genética , Cloruro de Sodio/farmacología , Animales , Secuencia de Bases , Presión Sanguínea/efectos de los fármacos , Resistencia a Medicamentos/genética , Femenino , Hipertensión/inducido químicamente , Masculino , Sondas Moleculares/genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Ratas , Ratas Mutantes/fisiologíaAsunto(s)
Fosfatasa Alcalina/genética , Cristalinas/genética , Genes , Inhibinas/genética , Antígenos Comunes de Leucocito/genética , Ratas/genética , Renina/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Animales , Mapeo Cromosómico , Cruzamientos Genéticos , Humanos , Escala de Lod , Ratones/genética , Proteína Fosfatasa 1 , Ratas Endogámicas Lew , Ratas Endogámicas SHR , Ratas Endogámicas , Especificidad de la EspecieRESUMEN
In the rat, the results of genetic linkage studies by "candidate" gene or "positional mapping" approaches have suggested that DNA sequences that regulate blood pressure may be located in the vicinity of the kallikrein gene family on chromosome 1, the gene for angiotensin-converting enzyme on chromosome 10, the renin gene on chromosome 13, and the major histocompatibility complex on chromosome 20. Some studies have also suggested that blood pressure regulatory genes may be located on the sex chromosomes. Pending the results of confirmatory studies, these experiments should be interpreted with caution. However, with confirmation of these studies, it should be possible to create a variety of new animal models that will provide excellent opportunities for investigating the molecular, biochemical, and physiologic determinants of high blood pressure. In addition, in genetic studies in humans with essential hypertension, it may be worthwhile to target chromosome regions that are homologous to those implicated in linkage studies of hypertension in rodents. By narrowing the focus on selected areas of the genome, experimental linkage studies in the rat may also be used to guide the detailed molecular approaches ultimately required to identify the specific DNA sequence alterations that give rise to increased blood pressure.