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Next-generation sequencing facilitates quantitative analysis of hepatic sex-differences in ZSF1 rats

ABSTRACT: The aim of this study was to identify sex-specific hepatic genes in Zucker spontaneously hypertensive fatty rats (ZSF1), a rat model for diabetic nephropathy.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE57598 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA246761

REPOSITORIES: GEO

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Acetylation and phosphorylation changes to cardiac proteins in experimental HFpEF due to metabolic risk reveal targets for treatment

Project description:Aims: Despite the high prevalence of heart failure with preserved ejection fraction (HFpEF), the pathomechanisms remain elusive and specific therapy is lacking. Disease-causing factors include metabolic risk, notably obesity. However, proteomic changes in HFpEF are poorly understood, hampering therapeutic strategies. We sought to elucidate how metabolic syndrome affects cardiac protein expression, phosphorylation and acetylation in the Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 (ZSF1) rat HFpEF model, and to evaluate some changes regarding their potential for treatment. Main methods: ZSF1 obese and lean rats were fed a Purina diet up to the onset of HFpEF in the obese animals. We quantified the proteome, phosphoproteome and acetylome of ZSF1 obese versus lean heart tissues by mass spectrometry and singled out targets for site-specific evaluation. Key findings: We found the acetylome of ZSF1 obese versus lean hearts more severely altered (21% of proteins changed) than the phosphoproteome (9%) or proteome (3%). Proteomic alterations, confirmed by immunoblotting, indicated low-grade systemic inflammation and endothelial remodeling in obese hearts, but low nitric oxide-dependent oxidative/nitrosative stress. Altered acetylation in ZSF1 obese hearts mainly affected pathways important for metabolism, energy production and mechanical function, including hypo-acetylation of mechanical proteins but hyper-acetylation of proteins regulating fatty acid metabolism. Hypo-acetylation and hypo-phosphorylation of elastic titin in ZSF1 obese hearts explained myocardial stiffening. Significance: Cardiometabolic syndrome alters posttranslational modifications, notably acetylation, in experimental HFpEF. Pathway changes implicate a HFpEF signature of low-grade inflammation, endothelial dysfunction, metabolic and mechanical impairment, and suggest titin stiffness and mitochondrial metabolism as promising therapeutic targets.

2022-10-12 | PXD036259 | Pride

RNA-Seq analysis of kidney transcriptome profiles in young spontaneously hypertensive rats and revealing the protective effects and potential therapeutic targets of SGLT2 inhibitors in early hypertensive nephropathy

Project description:Hypertensive nephropathy is a common complication of hypertension that places a heavy burden on society. SGLT2 inhibitors are a new class of hypoglycemic agents that have been shown to have specific protective effects on the kidneys. This study aimed to investigate the early changes in renal transcription spectrum in spontaneously hypertensive rats and the effects of DAPA, a sodium-glucose cotransporter 2 inhibitor, on the remission of hypertensive nephropathy and its underlying molecular mechanisms. We furthermore show thatSGLT2 inhibitors may reduce inflammation and improve energy metabolism by regulating the expression of SLC9a3, Zbtb20, Trim50 and Ccnl2.

2024-06-30 | GSE207191 | GEO

Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction

Project description:Microvascular dysfunction has been proposed to drive heart failure with preserved ejection fraction (HFpEF), but the initiating molecular and cellular events are largely unknown. Our objective was to determine when microvascular alterations in HFpEF begin, how they contribute to disease progression, and how pericyte dysfunction plays a role herein. We aimed to assess microvascular dysfunction with respect to the development of cardiac dysfunction, in the Zucker fatty and spontaneously hypertensive (ZSF1) obese rat model of HFpEF at three time points: 6, 14, and 21 weeks of age. We found that pericyte loss was the earliest and strongest microvascular change, occurring before prominent echocardiographic signs of diastolic dysfunction were present. Pericytes were shown to be less proliferative and had a disrupted morphology at 14 weeks in the obese ZSF1 animals, who also exhibited an increased capillary luminal diameter and disrupted endothelial junctions. Pericytes exposed to oxidative stress in vitro showed downregulation of cell cycle associated pathways, and induced a pro-inflammatory state in endothelial cells upon co-culture. We propose pericytes are important for maintaining endothelial cell function, where loss of pericytes enhances the reactivity of endothelial cells to inflammatory signals and promotes microvascular dysfunction, thereby accelerating the development of HFpEF.

2023-12-29 | GSE251995 | GEO

Molecular studies on sex-different control of the hepatic metabolism in relations to insulin sensitivity (set 2)

Project description:In this study we have analyzed gene expression and metabolite levels in the livers of male and female Zucker diabetic fatty (ZDF) rats. We speculated that the sex different development of diabetes in the ZDF animals presents the opportunity to relate gender to diabetes (since only males become diabetic on normal diet). In this model one can search for parameters that distinguish females fed normal diet compared to high fat diet (i.e. components that vary with the development of diabetes) and evaluate if such changes can be related to components that characterize male diabetic animals..

2011-08-10 | GSE23809 | GEO

Molecular studies on sex-different control of the hepatic metabolism in relations to insulin sensitivity (set 1)

2011-08-10 | GSE23808 | GEO

Transcription profiling of rat adrenal tissue to identify gene expression differences in spontaneously hypertensive rats (SHR), normotensive rats (BN) and recombinant inbred strains

Project description:We aimed to identify gene expression profiles/differences between spontaneously hypertensive rat(SHR) and normotensive rat (BN) in a set of recombinant inbred (RI) strains.

2008-04-18 | E-TABM-457 | biostudies-arrayexpress

Molecular studies on sex-different control of the hepatic metabolism in relations to insulin sensitivity (set 1)

2011-08-09 | E-GEOD-23808 | biostudies-arrayexpress

Molecular studies on sex-different control of the hepatic metabolism in relations to insulin sensitivity (set 2)

2011-08-09 | E-GEOD-23809 | biostudies-arrayexpress

Effect of Soluble Guanylyl Cyclase Stimulator Compound 1 on Renal function in ZSF-1 model of diabetic nephropathy

Project description:Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator, Compound 1, can enhance NO signaling, reduce proteinuria in diabetic nephropathy pre-clinical model with diminished NO-bioavailability and increased oxidized sGC. We therefore, evaluated the effect of sGC stimulator Compound 1 on renal effect in obese ZSF1 rats. Materials and Methods: The sGC stimulator Compound 1, the standard of care agent enalapril, and combination of Compound 1 with enalapril was administered chronically to ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for estimate glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. Histopathology of glomerular and interstitial lesions were assessed at the completion of the study. Results: While both Compound 1 and Enalapril significantly reduced blood pressure the combination of Compound 1 and enalapril normalized blood pressure level. Compound 1 improved eGFR and reduced UPCR and UACR. Combination of enalapril and Compound 1 resulted in marked reduction in UPCR and UACR and improved GFR. Conclusion: The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression and the combination of sGC stimulator with enalapril provided a greater renal protection in a rodent model of diabetic nephropathy.

2021-08-02 | GSE179405 | GEO

Transcriptomic profiling of diabetic rats treated with peripherical focused ultrasound (pFUS)

Project description:To better characterize the systemic response of diabetic rats to daily hepatoportal pFUS stimulation, we conducted transcriptomic profiling of different metabolic tissues by RNAseq. For this purpose, we included samples from liver, intestines, kidney, adipose, muscle, pancreas, hypothalamus and blood in the Zucker diabetic fatty (ZDF) and diet induced obese (DIO) rodent models. ZDF rats spontaneously develop type 2 diabetes (T2D) as a result of a missense mutation (fatty, fa) in the leptin receptor gene and develop moderate hyperglycemia spontaneously as a result of the insulin resistance and pancreatic insufficiency. DIO model uses a high fat/high carbohydrate diet to induce obesity and insulin resistance. Following development of obesity low dose streptozotocin (STZ) is used to induce a moderate level of pancreatic beta cell death which impairs insulin secretion similar to that seen in later stage T2D. Tissue samples were processed and analyzed after 3 days, 4 weeks, and 7 weeks of 3 minute per day pFUS treatments. All procedures performed were done in accordance with the National Institutes of Health (NIH) Guidelines under protocols approved by the Institutional Animal Care and Use Committee (IACUC) of GE Global Research.

2022-03-31 | GSE197097 | GEO

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