Effect of Soluble Guanylyl Cyclase Stimulator Compound 1 on Renal function in ZSF-1 model of diabetic nephropathy
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ABSTRACT:
PROVIDER: PRJNA743569 | ENA |
REPOSITORIES: ENA
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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
Project description:The aberrant activation of the ERG oncogenic pathway due to TMPRSS2-ERG gene fusions is the major driver of prostate cancer initiation and progression. We identified the alpha1 and beta1 subunits of soluble guanylyl cyclase (GUCY1A1, GUCY1B1) as major ERG-regulated genes in prostate cancer cells. Soluble guanylyl cyclase (sGC) is the major mediator of nitric oxide signaling in cells that, upon nitric oxide binding, catalyzes the synthesis of cGMP and subsequently activates PKG. We showed in ERG-positive PCa cells (VCaP) that cGMP synthesis was significantly elevated by ERG, leading to increased PKG activity and cell proliferation. To further understand the functions of sGC-cGMP pathway in prostate cancer cells, we performed RNA-seq analyses in VCaP cells to identify genes that are regulated by sGC.
2018-05-22 | GSE114738 | GEO
Project description:Genomic and behavioral investigations were performed to determine the effects of a mutation in a Drosophila soluble guanylyl cyclase gene. A mutant DGCalpha1[3] third chromosome was crossed into a natural rover (for[R]) or natural sitter (for[s]) genetic background. (See Osborne et al. 1997; PMID: 9242616.) First instar larvae were collected and grown on 60mm Petri plates containing 10 mL of food until mid-third instar. (Approximate density was 3 animals per mL food). Larvae were collected and washed quickly with distilled water and were flash frozen in liquid nitrogen. Co-reared larvae were tested for behavioural effects. Four independent collections were made for each of the two conditions (Rover_DGCalpha1[3] or sitter_DGCalpha1[3]). Keywords = Drosophila Keywords = foraging Keywords = behavior Keywords = cGMP Keywords = guanylyl cyclase Keywords = genetic background
2010-06-10 | E-GEOD-2136 | biostudies-arrayexpress
Project description:Genomic and behavioral investigations were performed to determine the effects of a mutation in a Drosophila soluble guanylyl cyclase gene. A mutant DGCalpha1[3] third chromosome was crossed into a natural rover (for[R]) or natural sitter (for[s]) genetic background. (See Osborne et al. 1997; PMID: 9242616.) First instar larvae were collected and grown on 60mm Petri plates containing 10 mL of food until mid-third instar. (Approximate density was 3 animals per mL food). Larvae were collected and washed quickly with distilled water and were flash frozen in liquid nitrogen. Co-reared larvae were tested for behavioural effects. Four independent collections were made for each of the two conditions (Rover_DGCalpha1[3] or sitter_DGCalpha1[3]). Keywords = Drosophila Keywords = foraging Keywords = behavior Keywords = cGMP Keywords = guanylyl cyclase Keywords = genetic background Keywords: other
2005-05-01 | GSE2136 | GEO
Project description:Genes regulated by soluble guanylyl cyclase in VCaP prostate cancer cells
| PRJNA472401 | ENA
Project description:Total RNA were extracted from Guanylate Cyclase Soluble Subunit Beta-3 (GUCY1B3) overexpression U87 MG stable cell lines and U87 MG cells. Three RNA samples of each of the two cell lines were used for microarray analysis to compare gene expression profile Guanylate Cyclase Soluble Subunit Beta-3 (GUCY1B3) was cloned into pCDNA3.1D/V5-His-TOPO plasmid (Invitrgen) and then transfected into U87 MG (ATCC HTB-1) cells to generate stable overexpression cells. RNA from the stable cell lines and U87 MG were used for microarray
2016-06-15 | E-GEOD-83344 | biostudies-arrayexpress
Project description:Total RNA were extracted from Guanylate Cyclase Soluble Subunit Beta-3 (GUCY1B3) overexpression U87 MG stable cell lines and U87 MG cells. Three RNA samples of each of the two cell lines were used for microarray analysis to compare gene expression profile
2016-06-15 | GSE83344 | GEO
Project description:Stone1996 - activation of soluble guanylate
cyclase by nitric oxide
This features the two step binding of
NO to soluble Guanylyl Cyclase as proposed by
Stone
JR, Marletta MA. Biochemistry (1996) 35(4):1093-9 . There is a
fast step binding scheme and a slow step binding scheme. The
difference lies in the binding of a NO to a non-heme site on sGC,
which may not necessarily be the same site of binding during the
initial binding. The rates have been directly used models.
This model is described in the article:
Spectral and kinetic studies
on the activation of soluble guanylate cyclase by nitric
oxide.
Stone JR, Marletta MA.
Biochemistry 1996 Jan; 35(4):
1093-1099
Abstract:
The soluble form of guanylate cyclase (sGC) is the only
definitive receptor for the signaling agent nitric oxide (.NO).
The enzyme is a heterodimer of homologous subunits in which
each subunit binds 1 equiv of 5-coordinate high-spin heme. .NO
increases the Vmax of sGC up to 400-fold and has previously
been shown to bind to the heme to form a 5-coordinate complex.
Using stopped-flow spectrophotometry, it is demonstrated that
the binding of .NO to the heme of sGC is a complex process. .NO
first binds to the heme to form a 6-coordinate nitrosyl
complex, which then converts to a 5-coordinate nitrosyl complex
through one of two ways. For 28 +/- 4% of the heme, the
6-coordinate nitrosyl complex rapidly (approximately 20 s-1)
converts to the 5-coordinate complex. For the remaining 72 +/-
4% of the heme, the conversion of the 6-coordinate nitrosyl
complex to a 5-coordinate nitrosyl complex is slow (0.1-1.0
s-1) and is dependent upon the interaction of .NO with an
unidentified non-heme site on the protein. The heme (200 nM)
was completely converted to the 5-coordinate state with as
little as 500 nM .NO, and the equilibrium dissociation constant
of .NO for activating the enzyme was determined to be < or =
250 nM. Gel-filtration analysis indicates that the binding of
.NO to the heme has no effect on the native molecular mass of
the protein. Correlation of electronic absorption spectra with
activity measurements indicates that the 5-coordinate nitrosyl
form of the enzyme is activated relative to the resting
5-coordinate ferrous form of the enzyme.
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2008-10-21 | BIOMD0000000198 | BioModels
Project description:Hypertension is a dominating risk factor for cardiovascular disease. To characterize the genomic response to hypertension, we administered vehicle or angiotensin II to mice and performed gene expression analyses. AngII treatment resulted in a robust increase in blood pressure and altered expression of 235 genes in the aorta, including Gucy1a3 and Gucy1b3 which encode subunits of soluble guanylyl cyclase (sGC). Western blotting and immunohistochemistry confirmed repression of sGC associated with curtailed relaxation via sGC activation. Analysis of transcription factor binding motifs in promoters of differentially expressed genes identified enrichment of motifs for RBPJ, a component of the Notch signaling pathway, and the Notch coactivators FRYL and MAML2 were reduced. Gain and loss of function experiments demonstrated that JAG/NOTCH signaling controls sGC expression together with MAML2 and FRYL. Reduced expression of sGC, correlating with differential expression of MAML2 in stroke prone and spontaneously hypertensive rats was also seen and RNA-Seq data demonstrated correlations between JAG1, NOTCH3, MAML2 and FRYL and the sGC subunits GUCY1A3 and GUCY1B3 in human coronary artery. Notch signaling thus provides a constitutive drive on expression of the major nitric oxide receptor (GUCY1A3/GUCY1B3) in arteries from mice, rats, and humans, and this control mechanism is disturbed in hypertension.
2017-05-01 | GSE93597 | GEO
Project description:Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development is hampered by our incomplete understanding of animal models on a cellular level. We show that ZSF1 rats recapitulate human DKD on a phenotypic and transcriptomic level. Tensor decomposition prioritizes proximal tubule (PT) and stroma as phenotype-relevant cell types exhibiting a continuous lineage relationship. As DKD features endothelial dysfunction, oxidative stress, and nitric oxide depletion, soluble guanylate cyclase (sGC) is a promising DKD drug target. sGC expression is specifically enriched in PT and stroma. In ZSF1 rats, pharmacological sGC activation confers considerable benefits over stimulation and is mechanistically related to improved oxidative stress regulation, resulting in enhanced downstream cGMP effects. Finally, we define sGC gene co-expression modules, which allow stratification of human kidney samples by DKD prevalence and disease-relevant measures such as kidney function, proteinuria, and fibrosis, underscoring the relevance of the sGC pathway to patients.
2023-02-24 | GSE209821 | GEO