Treatment effects of soluble guanylate cyclase modulation on diabetic kidney disease at single-cell resolution
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PROVIDER: PRJNA862532 | ENA |
REPOSITORIES: ENA
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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.
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2016-06-15 | E-GEOD-83344 | biostudies-arrayexpress
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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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2024-09-02 | BIOMD0000000198 | BioModels
Project description:The soluble guanylate cyclase stimulator praliciguat promotes ischemic leg reperfusion in leptin receptor-deficient mice
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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.
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Project description:Background: Moyamoya is a cerebrovascular condition of unknown mechanism characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICA) and the compensatory development of abnormal “moyamoya” vessels. It leads to ischemic and hemorrhagic stroke. We describe a novel autosomal recessive disease leading to severe moyamoya and early onset achalasia and report its cause in 3 unrelated families. Methods: We used a combination of genetic linkage and exome sequencing in 2 consanguineous to identify rare shared variants. Sanger sequencing of GUCY1A3, the sole gene mutated in both families, was then conducted in the third family. Platelets from one of the patients and controls were used to carry out functional studies. Results: Homozygous mutations of GUCY1A3 gene encoding the alpha1 subunit of soluble guanylate cyclase (sGC), the major receptor for Nitric Oxide (NO), were identified in all 3 families. Platelet analysis showed a complete loss of the mutated protein and showed an unexpected stimulatory role of sGC within platelets. Conclusion: The NO/sGC/cGMP pathway is a major pathway controlling vascular smooth muscle (VSMC) relaxation, vascular tone and vascular remodeling. Our data suggest that alterations of this pathway may lead to an abnormal vascular remodeling process in sensitive vascular areas with low blood
2014-06-19 | GSE48099 | GEO
Project description:To decipher the role of cGMP during the hypersensitive response Arabidopsis thaliana transgenic lines have been produced which express a rat soluble guanylate cyclase. Transgenic plants display a higher constitutive amount of cGMP (4 to 50 fold) compared to wild-type. Both GC and wt genotypes were infected with PstAvrB and transcriptome profile was analyzed at 12 hours post-infection.
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