Brown-Norway chromosome 1 mitigates the upregulation of proinflammatory pathways in mTAL cells and subsequent age-related CKD in Dahl SS/JrHsdMcwi rats.

IF 3.7 2区 医学 Q1 PHYSIOLOGY
Jacqueline M Chivers, Shannon A Whiles, Conor B Miles, Brianna E Biederman, Megan F Ellison, Connor W Lovingood, Marie H Wright, Donald B Hoover, Muhammad A Raafey, George A Youngberg, Manjeri A Venkatachalam, Nadezhda N Zheleznova, Chun Yang, Pengyuan Liu, Alison J Kriegel, Allen W Cowley, Paul M O'Connor, Maria M Picken, Aaron J Polichnowski
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引用次数: 0

Abstract

Chronic kidney disease (CKD) has a strong genetic component; however, the underlying pathways are not well understood. Dahl salt-sensitive (SS)/Jr rats spontaneously develop CKD with age and are used to investigate the genetic determinants of CKD. However, there are currently several genetically diverse Dahl SS rats maintained at various institutions and the extent to which some exhibit age-related CKD is unclear. We assessed glomerulosclerosis (GS) and tubulointerstitial fibrosis (TIF) in 3- and 6-mo-old male and female SS/JrHsdMcwi, BN/NHsd/Mcwi [Brown-Norway (BN)], and consomic SS-Chr 1BN/Mcwi (SS.BN1) rats, in which chromosome 1 from the BN rat was introgressed into the genome of the SS/JrHsdMcwi rat. Rats were fed a 0.4% NaCl diet. GS (31 ± 3% vs. 7 ± 1%) and TIF (2.3 ± 0.2 vs. 0.5 ± 0.1) were significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi rats, and CKD was exacerbated in males. GS was minimal in 6- and 3-mo-old BN (3.9 ± 0.6% vs. 1.2 ± 0.4%) and SS.BN1 (2.4 ± 0.5% vs. 1.0 ± 0.3%) rats, and neither exhibited TIF. In SS/JrHsdMcwi and SS.BN1 rats, mean arterial blood pressure was significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi (162 ± 4 vs. 131 ± 2 mmHg) but not SS.BN1 (115 ± 2 vs. 116 ± 1 mmHg) rats. In 6-mo-old SS/JrHsdMcwi rats, blood pressure was significantly greater in females. RNA-sequencing analysis revealed that inflammatory pathways were upregulated in isolated medullary thick ascending tubules in 7-wk-old SS/JrHsdMcwi rats, before the development of tubule pathology, compared with SS.BN1 rats. In summary, SS/JrHsdMcwi rats exhibit robust age-related progression of medullary thick ascending limb abnormalities, CKD, and hypertension, and gene(s) on chromosome 1 have a major pathogenic role in such changes.NEW & NOTEWORTHY This study shows that the robust age-related progression of kidney disease in Dahl SS/JrHsdMcw rats maintained on a normal-salt diet is abolished in consomic SS.BN1 rats. Evidence that medullary thick ascending limb segments of SS/JrHsdMcw rats are structurally abnormal and enriched in proinflammatory pathways before the development of protein casts provides new insights into the pathogenesis of kidney disease in this model.

布朗-诺威染色体 1 可减轻 Dahl SS/JrHsdMcwi 大鼠 mTAL 细胞中促炎通路的上调以及随后出现的与年龄相关的慢性肾脏病。
慢性肾脏病(CKD)有很强的遗传因素,但其潜在的发病途径还不十分清楚。达氏盐敏感(SS)/Jr 大鼠会随着年龄的增长自发患上慢性肾脏病,并被用于研究慢性肾脏病的遗传决定因素。然而,目前不同机构饲养着几种不同基因的 Dahl SS 大鼠,其中一些大鼠表现出与年龄相关的慢性肾脏病的程度尚不清楚。我们评估了 3 和 6 月龄雄性和雌性 SS/JrHsdMcwi、BN/NHsd/Mcwi [Brown-Norway (BN)] 和同源 SS-Chr 1BN/Mcwi (SS.BN1) 大鼠的肾小球硬化 (GS) 和肾小管间质纤维化 (TIF)。大鼠以 0.4% 的 NaCl 食物喂养。与 3 个月大的 SS/JrHsdMcwi 大鼠相比,6 个月大的 SS/JrHsdMcwi 大鼠的 GS(31 ± 3% vs. 7 ± 1%)和 TIF(2.3 ± 0.2 vs. 0.5 ± 0.1)显著增加,雄性大鼠的 CKD 加剧。6月龄和3月龄的BN(3.9 ± 0.6% vs. 1.2 ± 0.4%)和SS.BN1(2.4 ± 0.5% vs. 1.0 ± 0.3%)大鼠的GS极小,且均未表现出TIF。在 SS/JrHsdMcwi 和 SS.BN1 大鼠中,6 个月大的 SS/JrHsdMcwi 大鼠的平均动脉血压显著高于 3 个月大的 SS/JrHsdMcwi 大鼠(162 ± 4 vs. 131 ± 2 mmHg),而 SS.BN1 大鼠的平均动脉血压则不显著(115 ± 2 vs. 116 ± 1 mmHg)。在 6 个月大的 SS/JrHsdMcwi 大鼠中,雌性大鼠的血压明显更高。RNA 序列分析表明,与 SS.BN1 大鼠相比,7 周大的 SS/JrHsdMcwi 大鼠在发生肾小管病变之前,离体髓质粗升小管中的炎症通路上调。总之,SS/JrHsdMcwi 大鼠表现出与年龄相关的髓质粗升支异常、慢性肾功能衰竭和高血压,而 1 号染色体上的基因在这些变化中起着主要的致病作用。这项研究表明,以正常盐饮食饲养的 Dahl SS/JrHsdMcw 大鼠肾脏疾病与年龄相关的进展在同体 SS.BN1 大鼠中消失。有证据表明,SS/JrHsdMcw 大鼠的髓质增厚升支肢段结构异常,并在出现蛋白尿之前富含促炎症通路,这为该模型肾脏疾病的发病机制提供了新的见解。
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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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