Brown-Norway chromosome 1 mitigates the upregulation of pro-inflammatory pathways in mTAL cells and subsequent age-related CKD in Dahl SS/JrHsdMcwi Rats. Journal Article

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Authors: Chivers, JM; Whiles, SA; Miles, CB; Biederman, BE; Ellison, MF; Lovingood, CW; Wright, MH; Hoover, DB; Raafey, MA; Youngberg, GA; Venkatachalam, MA; Zheleznova, NN; Yang, C; Liu, P; Kriegel, AJ; Cowley, AW; O'Connor, PM; Picken, MM; Polichnowski, AJ
Article Title: Brown-Norway chromosome 1 mitigates the upregulation of pro-inflammatory pathways in mTAL cells and subsequent age-related CKD in Dahl SS/JrHsdMcwi Rats.
Abstract: Chronic kidney disease (CKD) has a strong genetic component; however, the underlying pathways are not well understood. Dahl 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-month-old male and female SS/JrHsdMcwi, BN/NHsd/Mcwi (Brown-Norway (BN)), and consomic SS-Chr 1/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- vs. 3-month-old SS/JrHsdMcwi rats, and CKD was exacerbated in males. GS was minimal in 6- and 3-month-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 (BP) was significantly greater in 6- vs. 3-month-old SS/JrHsdMcwi (162±4 vs. 131±2 mmHg) but not SS.BN1 (115±2 vs. 116±1 mmHg) rats. In 6-month-old SS/JrHsdMcwi rats, BP was significantly greater in females. RNAseq analysis revealed that inflammatory pathways were upregulated in isolated medullary thick ascending (mTAL) tubules in 7-week-old SS/JrHsdMcwi rats, prior to the development of tubule pathology, vs. SS.BN1 rats. In summary, SS/JrHsdMcwi rats exhibit robust age-related progression of mTAL abnormalities, CKD, and hypertension, and gene(s) on chromosome 1 have a major pathogenic role in such changes.
Journal Title: American journal of physiology. Renal physiology
Publisher: Unknown  
Date Published: 2022