Research Project
10471535
We seek to continue the remarkable series of insights that have emerged from our genetic studies in a rat model of hypertension-associated renal disease. This model acquires disease susceptibility from natural genetic variation. Our progress in uncovering and proving the causative genetic variation indicates that the final mediator of hypertensive renal injury is the genetically determined formation of pathogenic antibodies. While pathogenic antibodies have been implicated in rarer forms of kidney disease, they have not been implicated in human hypertensive disease, neither have they been excluded from such disease. In part, this may be because our work shows that genetic variation in the gene encoding immunoglobulin (IGH) makes a major contribution to disease risk. This large gene (1.2Mb in humans) contains extraordinary levels of structural diversity in both rats and humans. As a result, GWAS genotyping platforms drastically under-represent IGH variation and the presence of phenotypically important structural variation in IGH cannot be adequately considered. The rat model we use therefore, provides a tool to investigate the role of genetic variation in immunoglobulin in the pathogenesis of renal injury in hypertension that is not currently accessible in human population genetics. In the present study we will exploit inbred congenic hypertensive rat lines we have constructed to understand how genetic variation creates a pathogenic mechanism of disease. We will first seek out the source of antigens that elicit disease-causing antibodies. We have developed evidence of bacterial origin of these antigens and will investigate gut bacterial translocation. We will then investigate the target of pathogenic antibodies in order to link the alteration in renal function induced by elevated blood pressure with the emergence of disease in the presence of genetic susceptibility. We believe these studies can guide a pathway to explore and investigate analogous mechanisms of disease pathogenesis in humans.
