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

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-09-01 Epub Date: 2023-07-13 DOI:10.1152/ajprenal.00058.2023
Isha S Dhande, Yaming Zhu, Aniket S Joshi, M John Hicks, Michael C Braun, Peter A Doris
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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.NEW & NOTEWORTHY Here, we used a polygenic animal model of hypertensive renal disease to show that genetic variation affecting antibody formation underlies hypertensive renal disease. We proved the genetic thesis by generating an immunoglobulin knockout in the susceptible animal model.

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影响抗体形成的多基因遗传变异是易中风自发性高血压大鼠高血压肾损伤的基础。
在自发性高血压大鼠(SHR)的发育过程中,产生了几个不同但密切相关的品系。大多数品系对高血压肾病具有耐药性。然而,SHR-A3系(易中风的SHR)经历了末端器官损伤(EOI),并提供了一个可用于揭示遗传原因的损伤易感性模型。在本研究中,我们产生了一个同源系,其中SHR-A3中的三个不同的疾病基因座同时被来自抗损伤SHR系(SHR-B2)的同源基因座取代。通过全基因组测序验证了在这个三同源系[SHR-A3(Trip B2)]中所有三个基因座都被纯合取代,同时SHR-A3的遗传背景被完全保留。同源基因替换对收缩压没有影响[198.9 ± 3.34 mmHg,平均值±SE,SHR-A3(跳闸B2)=194.7 ± 2.55毫米汞柱]。SHR-A3(Trip B2)动物的肾损伤指标(蛋白尿、组织学损伤评分和尿液生物标志物水平)降低,尽管SHR-B2基因组的2.8G碱基中只有4.5M碱基(占基因组的0.16%)转移到同源系中。三个同源基因座的基因含量和基因多态性的功能效应表明免疫球蛋白在EOI发病机制中的作用。为了证明抗体在SHR-A3 EOI中的作用,我们产生了一个SHR-A3系,其中免疫球蛋白重链基因的表达被敲除(SHR-A3-IGHKO)。SHR-A3-IGHKO系的动物缺乏B细胞和免疫球蛋白,但高血压表型不受影响。然而,肾损伤在这一行中减少了,证实了免疫球蛋白在该遗传风险模型中的高血压EOI中的致病作用。新的和值得注意的是,我们使用了高血压肾病的多基因动物模型来表明影响抗体形成的基因变异是高血压肾病的基础。我们通过在易感动物模型中产生免疫球蛋白敲除来证明这一遗传学论点。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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