NADPH Oxidase 4 and Metabolic Stress in Dahl Salt-Sensitive Rat Kidneys
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE298727 | GEO | 2026/05/07
REPOSITORIES: GEO
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Project description:The body's circadian rhythm is coordinated by a central hypothalamic and peripheral molecular clocks, which involve clock proteins (PER, CRY, CLOCK, and BMAL1). Our recent study demonstrated that deletion of Per1 in Dahl salt-sensitive (SS) rats (SSPer1-/-) exacerbated SS hypertension (HTN), kidney injury, and disrupted blood pressure rhythms. To define time-of-day, genotype-, and diet-dependent alterations in the renal transcriptome and proteome associated with SS HTN, we collected kidney cortex from SS and SSPer1-/- rats fed either a normal salt (NS, 0.4% NaCl) or high salt (HS, 4% NaCl) diet. Samples were obtained during both the active (night) and inactive (day) phases. The diet challenges were conducted for 3 weeks in male rats. Bulk RNA-sequencing was performed on both NS and HS-fed groups, and proteomic analyses were performed in HS-fed groups. In SS rats, HS intake markedly blunted time-of-day-dependent transcriptional changes, including reduced differential expression of core circadian genes such as Bmal1 and Nr1d1 when transitioning from the inactive to the active phase. Pathway analyses revealed significant stress and immune response, as well as metabolic adaptations caused by the HS diet. Specifically, the remodeling of the pyruvate dehydrogenase complex was identified as a key prediction in both transcriptomic and phosphoproteomic datasets. As anticipated, Per1 deletion further exacerbated disruptions in immune regulation and metabolic adaptation. Collectively, our findings demonstrate that numerous renal genes exhibit diurnal oscillations under physiological conditions and are profoundly disrupted in SS HTN, likely contributing to impaired kidney function and circadian misalignment of blood pressure regulation.
2025-12-01 | GSE311806 | GEO
Project description:Regulated endocrine specific protein 18 (Resp18), expression has been specifically located in a series of tissues and cell types however the exact cellular function is unknown. In previous studies we have showed that a targeted disruption of Resp18 in Dahl SS rats (Resp18mutant) resulted in higher blood pressure (BP), increased renal fibrosis, and decreased survival rate on a long term (6-week) 2% high salt (HS) diet treatment compared with wild type SS rats. In the current study we studied whether a short term (1 week) exposure to HS diet shows a similar effect in Resp18mutant rats. Furthermore, previously we have shown that in addition to BP phenotype Resp18mutant rats have demonstrated deteriorative kidney phenotype evident through renal fibrosis, protein urea and protein cast formation. Based on this background we conducted BP study and performed transcriptomic profiling of the kidney after one-week exposure to HS diet treatment. Through radio-telemetry procedure, we found that the systolic BP was increased in the Resp18mutant rats compared with SS rats even with short term HS diet exposure. Therefore, we sought out to investigate if there was any alteration in the transcriptomic response by HS diet treatment in the Resp18mutant rat kidneys. Using RNA sequencing approach, we found that Resp18mutant rats showed a differential expression of 25 genes of which one was an upregulation of Ren. We confirmed the upregulation of Ren and other differentially expressed genes via qRT-PCR analysis. Upon KEGG pathway enrichment we found that the Resp18mutant rat showed upregulation in the renin angiotensin system (RAAS), and renin secretion pathway. Furthermore, the renin activity is found to be higher in Resp18mutant rats serum compared with SS rats. Therefore, these observations demonstrate that upon disruption of Resp18 gene in SS rats associated with the increase in renin secretion and thus increase BP.
2021-07-01 | GSE149006 | GEO
Project description:Background. The Dahl salt-sensitive (SS) rat is an established model of salt-sensitive hypertension and renal damage. Recently, sodium-independent dietary effects were shown to be important in the development of the SS hypertensive phenotype. Compared to Dahl SS/JrHsdMcwi (SS/MCW) rats fed a purified diet (AIN-76A), grain-fed Dahl SS/JrHsdMcwiCrl rats (SS/CRL; Teklad 5L2F) were less susceptible to salt-induced hypertension and renal damage. Methods. With the known role of the immune system in hypertension, the present study characterized the immune cells infiltrating SS/MCW and SS/CRL kidneys. To further identify distinct molecular pathways between SS/MCW and SS/CRL, transcriptomic analysis was performed via RNA sequencing in T-cells isolated from the blood and kidneys of low and high salt-fed rats. Results. Following a 3-week high salt (4.0% NaCl) challenge, SS/CRL rats were protected from salt-induced hypertension (116.5±1.2 vs 141.9±14.4 mmHg) and albuminuria (21.7±3.5 vs 162.9±22.2 mg/day) compared to SS/MCW. Additionally, the absolute number of immune cells infiltrating the kidney was significantly reduced in SS/CRL. RNA-seq revealed >50% of all annotated genes in the entire transcriptome to be significantly differentially expressed in T-cells isolated from blood versus kidney. Pathway analysis of significant differentially expressed genes between SS/MCW and SS/CRL renal and circulating T-cells demonstrated salt-induced changes in genes related to inflammation in SS/MCW compared to metabolism-related pathways in SS/CRL. Conclusions. These functional and transcriptomic T-cell differences between SS/MCW and SS/CRL show that sodium-independent dietary effects may influence the immune response and infiltration of immune cells into the kidney, ultimately impacting susceptibility to salt-induced hypertension and renal damage.
2019-08-26 | GSE127000 | GEO
Project description:Kidney injury mechanisms that develop in salt-sensitive (SS) hypertension are incompletely understood. Using the Dahl SS rat, which is a prominent model of salt-sensitive hypertension and associated kidney injury, loss of function of the pro-inflammatory transcription factor, ETS-1, corrects kidney microvascular autoregulatory dysfunction and injury. C-C motif chemokine ligand 2 (CCL2) is a direct target of ETS-1, so SS rats lacking Ccl2 (termed (SSCcl2 -/-) were therefore examined. Unlike SS rats, SSCcl2 -/- rats did not develop salt-sensitive hypertension, loss of autoregulation of afferent arterioles, or kidney injury. cDNA libraries from renal microvasculature of these rats was sequenced.
2026-04-02 | GSE298536 | GEO
Project description:Substitution of chromosome 13 from Brown Norway BN/SsNHsd/Mcw (BN/Mcw) rats into the Dahl salt-sensitive SS/JrHsd/Mcw (SS/Mcw) rats resulted in substantial reduction of blood pressure salt sensitivity in this consomic rat strain designated SSBN13. In the present study, we attempted to identify genes associated with salt-sensitive hypertension by utilizing a custom, known-gene cDNA microarray to compare the mRNA expression profiles in the renal medulla (a tissue playing a pivotal role in long-term blood pressure regulation) of SS/Mcw and SSBN13 rats on either low-salt (0.4% NaCl) or high-salt (4% NaCl, 2 wk) diets. Keywords: Dahl S rat; blood pressure; kidney; consomic rats
2005-11-17 | GSE3608 | GEO
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.
2024-07-10 | GSE269511 | GEO
Project description:The Dahl salt-sensitive (SS) rat is an established model of hypertension and renal damage that is accompanied with an activation of the immune system in the response to a high salt diet. Investigations into the effects of sodium-independent and –dependent components of the diet were shown to affect the disease phenotype with Dahl SS/JrHsdMcwi (SS/MCW) rats maintained on a purified diet (AIN-76A) presenting with a more severe phenotype relative to the grain-fed Dahl SS/JrHsdMcwiCrl rat (SS/CRL). Recently, T cells isolated from the kidneys of the two strains unveiled that transcriptomic and functional differences may contribute to the susceptibility of hypertension and renal damage. Since contributions of the immune system, environment and diet are documented to alter this phenotype, this present study examined the epigenetic profile of T cells isolated from the periphery and the kidney from these strains. In response to high salt challenge, the methylome of T cells isolated from the kidney of SS/MCW exhibit significantly more differentially methylated regions with a preference for hypermethylation compared to the SS/CRL kidney T cells. Circulating T cells exhibited similar methylation profiles between the strains. Utilizing transcriptomic data from T cells isolated from the same animals upon which the DNA methylation analysis was performed, a predominant negative correlation was observed between gene expression and DNA methylation in all groups. Lastly, inhibition of DNA methyltransferases blunted salt-induced hypertension and renal damage in the SS/MCW rats providing a functional role for methylation. The study demonstrated the influence of epigenetic modifications to immune cell function, highlighting the need for further investigations.
2019-06-10 | GSE132417 | GEO
Project description:Numerous adult diseases involving tissues that consist primarily of non-dividing cells are associated with changes in DNA methylation. It suggests a role for de novo methylation or demethylation of DNA, which is catalyzed by DNA methyltransferase 3 (Dnmt3) and ten-eleven translocases (Tet). However, the contribution of DNA de novo (de)methylation to these diseases remains nearly completely unproven. Broad changes in DNA methylation occurred within days in the renal outer medulla of Dahl SS rats fed a high-salt diet, a classic model of hypertension. Intra-renal administration of anti-Dnmt3a/Tet3 GapmeR’s attenuated high salt-induced hypertension in SS rats. The high salt diet induced differential expression of 1,712 genes in the renal outer medulla. Remarkably, the differential expression of 76% of these genes were prevented by anti-Dnmt3a/Tet3 GapmeR’s. The genes differentially expressed in response to the GapmeR’s were involved in the regulation of metabolism and inflammation and were significantly enriched for genes showing differential methylation in response to the GapmeR’s. These data indicate DNA de novo (de)methylation in the kidney contributes to the development of hypertension in SS rats. The findings should help to shift the paradigm of DNA methylation research in diseases involving non-dividing cells from correlative analysis to functional and mechanistic studies.
2019-02-13 | GSE114334 | GEO
Project description:Numerous adult diseases involving tissues that consist primarily of non-dividing cells are associated with changes in DNA methylation. It suggests a role for de novo methylation or demethylation of DNA, which is catalyzed by DNA methyltransferase 3 (Dnmt3) and ten-eleven translocases (Tet). However, the contribution of DNA de novo (de)methylation to these diseases remains nearly completely unproven. Broad changes in DNA methylation occurred within days in the renal outer medulla of Dahl SS rats fed a high-salt diet, a classic model of hypertension. Intra-renal administration of anti-Dnmt3a/Tet3 GapmeR’s attenuated high salt-induced hypertension in SS rats. The high salt diet induced differential expression of 1,712 genes in the renal outer medulla. Remarkably, the differential expression of 76% of these genes were prevented by anti-Dnmt3a/Tet3 GapmeR’s. The genes differentially expressed in response to the GapmeR’s were involved in the regulation of metabolism and inflammation and were significantly enriched for genes showing differential methylation in response to the GapmeR’s. These data indicate DNA de novo (de)methylation in the kidney contributes to the development of hypertension in SS rats. The findings should help to shift the paradigm of DNA methylation research in diseases involving non-dividing cells from correlative analysis to functional and mechanistic studies.
2019-02-13 | GSE114333 | GEO
Project description:Substitution of chromosome 13 from Brown Norway BN/SsNHsd/Mcw (BN/Mcw) rats into the Dahl salt-sensitive SS/JrHsd/Mcw (SS/Mcw) rats resulted in substantial reduction of blood pressure salt sensitivity in this consomic rat strain designated SSBN13. In the present study, we attempted to identify genes associated with salt-sensitive hypertension by utilizing a custom, known-gene cDNA microarray to compare the mRNA expression profiles in the renal medulla (a tissue playing a pivotal role in long-term blood pressure regulation) of SS/Mcw and SSBN13 rats on either low-salt (0.4% NaCl) or high-salt (4% NaCl, 2 wk) diets. To increase the reliability of microarray data, we designed a four-way comparison experiment incorporating several levels of replication and developed a conservative yet robust data analysis method. Using this approach, from the 1,751 genes examined (representing more than 80% of all currently known rat genes), we identified 80 as being differentially expressed in at least 1 of the 4 comparisons.
2010-06-30 | E-GEOD-3608 | biostudies-arrayexpress