RESUMEN
High blood pressure exerts its deleterious effects on health largely through acceleration of end-organ diseases. Among these, progressive loss of renal function is particularly important, not only for the direct consequences of kidney damage but also because loss of renal function is associated with amplification of other adverse cardiovascular outcomes. Genetic susceptibility to hypertension and associated end-organ disease is non-Mendelian in both humans and in a rodent model, the spontaneously hypertensive rat (SHR). Here, we report that hypertensive end-organ disease in the inbred SHR-A3 line is attributable to genetic variation in the immunoglobulin heavy chain on chromosome 6. This variation coexists with variation in a 10 Mb block on chromosome 17 that contains genetic variation in 2 genes involved in immunoglobulin Fc receptor signaling. Substitution of these genomic regions into the SHR-A3 genome from the closely related, but injury-resistant, SHR-B2 line normalizes both biomarker and histological measures of renal injury. Our findings indicate that genetic variation leads to a contribution by immune mechanisms hypertensive end-organ injury and that, in this rat model, disease is influenced by differences in germ line antibody repertoire.
Asunto(s)
Animales Congénicos/inmunología , Cromosomas de los Mamíferos , Hipertensión Renal , Hipertensión , Fragmentos Fc de Inmunoglobulinas , Riñón , Nefritis , Receptores Fc , Animales , Anticuerpos/sangre , Biomarcadores/sangre , Mapeo Cromosómico , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Hipertensión/diagnóstico , Hipertensión/genética , Hipertensión Renal/genética , Hipertensión Renal/inmunología , Hipertensión Renal/patología , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Riñón/inmunología , Riñón/patología , Nefritis/genética , Nefritis/inmunología , Nefritis/patología , Pronóstico , Sitios de Carácter Cuantitativo , Ratas , Ratas Endogámicas SHR , Receptores Fc/genética , Receptores Fc/inmunologíaRESUMEN
BACKGROUND: We have investigated serum levels of immunoreactive marinobufagenin (MBG) in 16- to 20-week-old spontaneously hypertensive rats (SHRs)-A3 and in the normotensive Wistar-Kyoto (WKY) rat strain in the absence of salt loading, and we have investigated the genetic control of serum MBG. METHODS AND RESULTS: We genotyped the F2 progeny of an SHR-A3×WKY intercross using a genome-wide panel of 253 single-nucleotide polymorphism markers that were dimorphic between SHR-A3 and WKY and measured serum MBG by ELISA. Serum MBG levels were lower in SHR-A3 than WKY rats (0.39±0.07 and 1.27±0.40 nmol/L, respectively), suggesting that MBG may not play a role in the markedly divergent blood pressure measured by telemetry in rats of these 2 strains (SHR-A3 and WKY, 198.3±4.43 and 116.8±1.51 mm Hg, respectively). The strain difference in serum MBG was investigated to determine whether genomic regions influencing MBG might be identified by genetic mapping. Quantitative trait locus mapping indicated a single locus influencing serum MBG in the region of chromosome 6q12. Homozygosity of WKY alleles at this locus was associated with increased serum MBG levels. We surveyed whole genome sequences from our SHR-A3 and WKY lines, seeking coding sequence variation between SHR-A3 and WKY within the mapped locus that might explain the inherited strain difference in serum MBG. CONCLUSIONS: We identified amino acid substitution in the sterol transport protein Abcg5, present in SHR-A3, but absent in WKY, that is a potential mechanism influencing MBG levels.