Polygenic genetic variation affecting antibody formation underlies hypertensive renal injury in the stroke-prone spontaneously hypertensive rat

Abstract

Most SHR lines are resistant to hypertensive renal disease. However, the SHR-A3 line (stroke-prone SHR or SHRSP) experiences end organ injury (EOI) and provides a model that can be used to uncover genetic causation. In the present study we have generated a congenic line in which three distinct disease loci in SHR-A3 are concurrently replaced with the homologous loci from an injury-resistant SHR line (SHR-B2). Verification that all three loci were homozygously replaced in this triple congenic line (SHR-A3(Trip B2)) while the genetic background of SHR-A3 was fully retained was obtained by whole genome sequencing. Congenic genome substitution was without effect on systolic blood pressure (198.9 ± 3.34 mmHg, mean ± SEM, SHR-A3(Trip B2) = 194.7 ± 2.55 mmHg). Measures of renal injury (albuminuria, histological injury scores and urinary biomarker levels) were reduced in SHR-A3(Trip B2) animals, even though only 4.5Mbases of the 2.8Gbases of the SHR-B2 genome (0.16% of the genome) was transferred into the congenic line. The gene content of the 3 congenic loci and the functional effects of gene polymorphism within suggest a role of immunoglobulin in EOI pathogenesis. To prove the role of antibodies in EOI in SHR-A3, we generated an SHR-A3 line in which expression from the immunoglobulin heavy (IGH) chain gene was knocked out. Animals in the SHR-A3-IGHKO line lack B cells and immunoglobulin, but the hypertensive phenotype is not affected. Renal injury, however, was reduced in this line confirming a pathogenic role for immunoglobulin in hypertensive EOI in this model of heritable risk.