Polygenic Genetic Variation Affecting Antibody Formation Underlies Hypertensive Renal Injury in the Stroke-Prone Spontaneously Hypertensive Rat

Authors

Isha S Dhande
Yaming Zhu
Aniket S Joshi
M John Hicks
Michael C Braun
Peter A Doris

Publication Date

9-1-2023

Journal

American Journal of Physiology-Renal Physiology

DOI

10.1152/ajprenal.00058.2023

PMID

37439198

PMCID

PMC10511163

PubMedCentral® Posted Date

9-1-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Kidney, Stroke, Hypertension, Hypertension, Renal, Blood Pressure, Rats, Antibody Formation, Nephritis, Rats, Inbred SHR, Animals, Genetic Variation, antibodies, genetics, hypertension, immune mechanisms, kidney disease

Abstract

During development of the spontaneously hypertensive rat (SHR), several distinct but closely related lines were generated. Most lines are resistant to hypertensive renal disease. However, the SHR-A3 line (stroke-prone SHR) experiences end-organ injury (EOI) and provides a model of injury susceptibility that can be used to uncover genetic causation. In the present study, we generated a congenic line in which three distinct disease loci in SHR-A3 are concurrently replaced with 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 ± SE, 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 4.5 Mbases of the 2.8 Gbases of the SHR-B2 genome (0.16% of the genome) was transferred into the congenic line. The gene content of the three 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 chain gene was knocked out (SHR-A3-IGHKO). 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.