Targeted disruption of regulated endocrine-specific protein (<i>Resp18</i>) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury

Kumarasamy, Sivarajan; Waghulde, Harshal; Cheng, Xi; Mell, Blair; Abhijith, Basrur; Ashraf, Usman; Atari, Ealla; Joe, Bina

doi:10.1152/physiolgenomics.00008.2018

Cited by 13 publications

(4 citation statements)

References 38 publications

(37 reference statements)

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“…Our findings also confirm previous observations regarding genetic differences between SS/JrHsd/ Mcwi and SS/Jr (38). Because the salt-sensitivity phenotype is preserved in the SS/JrHsd/Mcwi and SS/Jr strains (25,34), it is possible that these genotypic differences have contributed to the change in blood pressure phenotype in SS rats purchased from Envigo.…”

Section: Discussionsupporting

confidence: 91%

Salt-sensitive (Rapp) rats from Envigo spontaneously develop accelerated hypertension independent of ovariectomy on a low-sodium diet

Pai

West

Souza

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Inbred salt-sensitive (SS) rats developed by John Rapp and distributed by Harlan (SS/JrHsd) were shown to model ovariectomy-induced hypertension since on a low sodium (LS) diet, ovariectomized SS (SS-OVX) animals became hypertensive in contrast to their sham-operated (SS-SHAM) normotensive littermates. After Harlan merged with Envigo in 2015, inconsistencies in the LS normotensive phenotype were reported. To further investigate these inconsistencies, we studied the effects of ovariectomy on SS and salt-resistant (SR) rats purchased from Envigo (SS/JrHsd/Env) between 2015-2017. The mean arterial pressure (MAP) in SS rats on a LS diet exceeded 160 mmHg at 7 months old (mo). Ovariectomy at 3mo had no detectable effect on MAP from 4-7mo nor did ovariectomy at 1.5mo significantly affect MAP at 10mo [MAP (mmHg): SR-SHAM (n=7), 102±3; SR-OVX (n=6), 114±1; *SS-SHAM (n=7), 177±6; *SS-OVX (n=5), 190±12; *p<0.0001 vs. SR, same ovarian-status]. Whole genome sequencing revealed more genomic variants of SS/JrHsd/Env including single nucleotide and insertion deletion polymorphisms and higher heterozygous/homozygous ratios compared to the reference genome than for SS/JrHsd/Mcwi and SS/Jr rats, maintained in Milwaukee, WI and Toledo, OH, respectively, and which still exhibit normal blood pressure on a LS diet. These findings demonstrate the female SS/JrHsd/Env rat has genetically diverged from the original phenotype which was normotensive on a LS diet when the ovaries were intact but which rapidly developed hypertension when the ovaries were removed. Nonetheless, the SS/JrHsd/Env rat could be a valuable model that complements other animal models of spontaneous hypertension used to investigate mechanisms of essential hypertension.

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Section: Discussionsupporting

confidence: 91%

Salt-sensitive (Rapp) rats from Envigo spontaneously develop accelerated hypertension independent of ovariectomy on a low-sodium diet

Pai

West

Souza

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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“… 185 , 186 Resp18 , first identified as a gene coregulated with POMC , is downregulated by dopamine and is highly expressed in the diencephalon, suggesting a role in salt and water balance and/or feeding behavior; 185 indeed, a rat Resp18 KO line, although not evaluated for body fat, did show increased SBP. 187 PTPRN, also known as IA-2, is an autoantigen linked to T1D but not obesity, and published Ptprn KO mice have normal BW. 186 Surprisingly, KO lines for both genes had increased body fat in our agnostic screen, and in addition Resp18 KO mice had increased SBP (KO, n=8, 101±7 vs WT, n=4, 92±7 mmHg, P <0.05) supporting the finding in Resp18 KO rats.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Powell¹,

Revelli²,

Doree³

et al. 2021

DMSO

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Purpose Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000 TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat. Materials and Methods KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC). Results Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 ( Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1 ) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only. Conclusion These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.

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“…The results show that genes involved in regulating kidney function and homeostasis were significantly upregulated, including Slco1a6, Resp18, Tmigd1, Rbm3, Azgp1, Lpl, Casr, and Slco4c1 . Targeted disruption of the Resp18 locus in the SD rat increases salt-induced hypertension and associated renal damage [ 18 ]. TMIGD1 is a cell adhesion molecule that is expressed primarily by intestinal and renal epithelial cells and acts as an antioxidant stress protective agent [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional sequencing analysis reveals the potential use of deer antler for “tonifying the kidney and strengthening bone”

et al. 2022

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Background It is recorded in the Chinese Pharmacopoeia that deer antlers can be used to tonify the kidney and strengthen bone. Although numerous studies have demonstrated that deer antler has protective effects on the kidney and bone, its molecular mechanisms remain to be elucidated. The aim of this study was to explore the molecular mechanism underlying its effects on the bone and kidney. Methods Water extract of pilose antler was prepared and then filtered through a 0.45 μm Hollow Fiber Cartridge (GE Healthcare, USA). The filtrate was freeze-dried by a Heto PowerDry LL3000 Freeze Dryer (Thermo, USA) and stored at − 80 °C. Rats were treated with deer antler extract (DAE) prepared in advance, and gene regulatory network in the kidney and bone was detected by RNA-Seq technique. Micro-CT was used to detect bone trabecular formation, bone mineral density (BMD) and bone volume fraction (BV/TV). Results The results demonstrate that DAE could jointly heighten renal function by maintaining renal homeostasis, combating renal fibrosis, and reducing renal inflammation by regulating ion transport. Furthermore, DAE can strengthen the bone system by stimulating osteoblast differentiation and regulating bone regeneration and the bone marrow microenvironment. Micro-CT results confirmed that DAE can promote bone trabecular formation and increase BMD and BV/TV. We also identified many genes that can regulate both the kidney and bone simultaneously, which explained the theory of “kidney governing bone” at the molecular level and provided possible strategies for further application of this theory to treat diseases. Conclusions DAE enhances renal function, maintains renal homeostasis, positively regulates skeletal system development, and increases bone mineral density. The underlying mechanism involves improving the expression levels of functional genes involved in renal function and regulation and repair, as well as genes that positively regulate skeletal system development.

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Targeted disruption of regulated endocrine-specific protein (Resp18) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury

Cited by 13 publications

References 38 publications

Salt-sensitive (Rapp) rats from Envigo spontaneously develop accelerated hypertension independent of ovariectomy on a low-sodium diet

Salt-sensitive (Rapp) rats from Envigo spontaneously develop accelerated hypertension independent of ovariectomy on a low-sodium diet

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Transcriptional sequencing analysis reveals the potential use of deer antler for “tonifying the kidney and strengthening bone”

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