Dataset Information

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

ABSTRACT: Inbred salt-sensitive (SS) rats developed by John Rapp and distributed by Harlan (SS/JrHsd) were shown to model ovariectomy-induced hypertension because 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 and 2017. The mean arterial pressure (MAP) in SS rats on a LS diet exceeded 160 mmHg at 7 mo old. Ovariectomy at 3 mo had no detectable effect on MAP from 4 to 7 mo, nor did ovariectomy at 1.5 mo significantly affect MAP at 10 mo in either strain; only strain differences in MAP were observed [MAP: SR-SHAM ( n = 7 rats), 102?±?3 mmHg; SR-OVX ( n = 6 rats), 114?±?1 mmHg; SS-SHAM ( n = 7 rats), 177?±?6 mmHg; SS-OVX ( n = 5 rats), 190?±?12 mmHg; where P < 0.0001 vs. SR, same ovarian-status for SS-SHAM and SS-OVX, respectively]. Whole genome sequencing revealed more genomic variants of SS/JrHsd/Env, including single nucleotide and insertion deletion polymorphisms and higher heterozygous/homozygous ratios compared with 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 that 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 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.

SUBMITTER: Pai AV

PROVIDER: S-EPMC6295493 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Pai Amrita V AV West Crystal A CA A de Souza Aline M AM Cheng Xi X West David A DA Ji Hong H Wu Xie X Baylis Chris C Sandberg Kathryn K

American journal of physiology. Regulatory, integrative and comparative physiology 20180719 5

Inbred salt-sensitive (SS) rats developed by John Rapp and distributed by Harlan (SS/JrHsd) were shown to model ovariectomy-induced hypertension because 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 ...[more]

PMID: 30024774

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Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.

Dataset Information

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

Publications

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

Similar Datasets

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