Susceptibility to Hypertensive Renal Disease in the Spontaneously Hypertensive Rat Is Influenced by 2 Loci Affecting Blood Pressure and Immunoglobulin Repertoire

Abstract

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 Mbase block on chromosome 17 that contains genetic variation in two 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.

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains

“…It should also help us better understand the genetic basis for strain-related differences in mouse models of human disease. Allelic variants have been associated with differences in disease susceptibility of rats 44 and humans 21 .…”

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild‐derived and classical inbred mouse strains

“…Nevertheless, the partial documentation of the IGH loci reported here and the strain differences seen are sufficient to raise the possibility that the IGHV locus may contribute to strain‐related differences in mouse models of human disease. Allelic variants have been associated with differences in disease susceptibility of rats and humans . IGHV sequence variability might also contribute to the differences that have been reported in the susceptibility of inbred mouse strains to both infectious and autoimmune diseases …”

Genetic Susceptibility to Hypertension-Induced Renal Injury

“…Diabetes and hypertension are the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD), but little is known about the genes involved. The present study by Dhande et al 1 validated two regions of the genome that together completely account for CKD in Stroke-prone Spontaneously Hypertensive Rats (SpSHR). This study is highly significant since one in seven Americans have CKD, and the Medicaid costs for treatment of patients with ESRD and CKD are 34 and 64 billion dollars/yr., respectively.…”

“…6 Part of the difficulty in identifying the causal genes in previous studies is that the susceptible and resistant strains were chosen to maximize genetic diversity, so the number of potential sequence variants in candidate regions is overwhelming. An alternative approach taken in the present study by Dhande et al 1 was to use closely-related SpSHR (SHR-A3 in Dhande et al 1 ) and SHR (SHR-B2 in Dhande et al 1 ) as the susceptible and resistant strains. These strains were derived during the development of SHR by inbreeding a subline susceptible to stroke after the alleles for hypertension were fixed.…”