Abstract P230: Depletion Of Cyclic-gmp Levels And The Inhibition Of Cgks Activate P21 Cip1 /p27 Kip1 Pathways And Trigger High Blood Pressure With Renal Fibrosis And Dysfunction

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Subhankar Das ◽  
Kandasamy Neelamegam ◽  
Whitney N Peters ◽  
Ramu Periyasamy ◽  
Kailash N Pandey
Keyword(s):  
Blood Pressure ◽  
Guanylyl Cyclase ◽  
Renal Fibrosis ◽  
Gene Knockout ◽  
Protective Effects ◽  
Matrix Expansion ◽  
Gene Knockout Mice ◽  
Cell Cycle Regulatory Proteins ◽  
Natriuretic Peptide Receptor A ◽  
Dependent Protein

Targeted-deletion of Npr1 gene (coding for guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) exhibits hypertrophic and proliferative effects in target organs of Npr 1 gene-knockout mice. Fibrosis and hypertrophy are regulated by p21 Cip1 and p27 Kip1 , cell-cycle regulatory proteins that inhibit target cyclin and cyclin-dependent kinase (cyclin-CDK) complex. We examined the activation of CDK blocker (p21 Cip1 /p27 Kip1 ) in Npr1 gene-knockout (0-copy; Npr 1 -/- ) mice and guanylyl cyclase (GC) inhibitor, A71915-treated and cGMP-dependent protein kinase (cGK) inhibitor, Rp-8-Br-cGMPS (Rp)-treated wild-type 2-copy ( Npr 1 +/+ ) and gene-duplicated 4-copy ( Npr 1 ++/++ ) mice. Blood pressure (BP) was significantly higher in 0-copy mice (138.6 ± 3.1 mmHg) and lower in 4-copy mice (86.0 ± 2.8 mmHg) than 2-copy mice (102.2 ± 1.7 mmHg). Treatment with A71915 and Rp showed significant changes in BP in 2-copy mice but caused only small increase in 4-copy mice. We found a significant decrease in renal cGMP levels with diminished cGK activity in 0-copy mice (p<0.0001) as well as A71915-treated (p<0.001) and Rp-treated (p<0.05) 2-copy and 4-copy mice as compared with controls animals. While significant activation of p-Erk1/2 (3-fold), p-p38MAPK (4-fold), p21 Cip1 (6-fold), and p27 Kip1 (5-fold) occurred in 0-copy, A71915-treated 2-copy, and A71915-treated 4-copy mice but Rp treatment caused minimal changes compared to control mice. There were significant increases in the proinflammatory cytokines, including TNF-α (6-fold), and IL-6 (3-fold) and profibrotic cytokine TGF-β1 (4-fold) in plasma and kidneys of 0-copy and A791915-treated 2-copy mice, but less in A71915-treated 4-copy mice than controls. Progressive renal pathology, including fibrosis, mesangial matrix expansion, tubular hypertrophy, and perivascular infiltration were significantly scored in 0-copy and A71915-treated 2-copy mice, but did so minimally in 4-copy mice compared with controls. The present results suggest that Npr1 has a pivotal role in inhibiting the renal fibrosis and pathology and exerts renal protective effects through the cGMP/cGK axis by repressing the CDK inhibitors, p21 Cip1 and p27 Kip1 . This work was supported by NIH grant (HL062147).

scholarly journals Activation of IKK/NF-κB provokes renal inflammatory responses in guanylyl cyclase/natriuretic peptide receptor-A gene-knockout mice

2012 ◽  
Vol 44 (7) ◽  
pp. 430-442 ◽  
Author(s):  
Subhankar Das ◽  
Ramu Periyasamy ◽  
Kailash N. Pandey
Keyword(s):  
Natriuretic Peptide ◽  
Proinflammatory Cytokines ◽  
Guanylyl Cyclase ◽  
Renal Fibrosis ◽  
Gene Knockout ◽  
Mutant Mice ◽  
Pyrrolidine Dithiocarbamate ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A

The present study was aimed at determining the consequences of the disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene ( Npr1) on proinflammatory responses of nuclear factor kappa B, inhibitory kappa B kinase, and inhibitory kappa B alpha (NF-κB, IKK, IκBα) in the kidneys of mutant mice. The results showed that the disruption of Npr1 enhanced the renal NF-κB binding activity by 3.8-fold in 0-copy (−/−) mice compared with 2-copy (+/+) mice. In parallel, IKK activity and IκBα protein phosphorylation were increased by 8- and 11-fold, respectively, in the kidneys of 0-copy mice compared with wild-type mice. Interestingly, IκBα was reduced by 80% and the expression of proinflammatory cytokines and renal fibrosis were significantly enhanced in 0-copy mice than 2-copy mice. Treatment of 0-copy mice with NF-κB inhibitors andrographolide, pyrrolidine dithiocarbamate, and etanercept showed a substantial reduction in renal fibrosis, attenuation of proinflammatory cytokines gene expression, and significantly reduced IKK activity and IkBα phosphorylation. These findings indicate that the systemic disruption of Npr1 activates the renal NF-κB pathways in 0-copy mice, which transactivates the expression of various proinflammatory cytokines to initiate renal remodeling; however, inhibition of NF-κB pathway repairs the abnormal renal pathology in mutant mice.

scholarly journals Molecular and genetic aspects of guanylyl cyclase natriuretic peptide receptor-A in regulation of blood pressure and renal function

2018 ◽  
Vol 50 (11) ◽  
pp. 913-928 ◽  
Author(s):  
Kailash N. Pandey
Keyword(s):  
Blood Pressure ◽  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Natriuretic Peptides ◽  
Molecular Mechanisms ◽  
Phenotypic Characterization ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Regulation Of Blood Pressure

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.

Protective effects of sunscreening agents on photocarcinogenesis, photoaging, and DNA damage in XPA gene knockout mice

2000 ◽  
Vol 292 (10) ◽  
pp. 511-518 ◽  
Author(s):  
S. Horiki ◽  
H. Miyauchi-Hashimoto ◽  
K. Tanaka ◽  
O. Nikaido ◽  
T. Horio
Keyword(s):  
Dna Damage ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Protective Effects ◽  
Sunscreening Agents ◽  
Gene Knockout Mice

P0984SGLT2 INHIBITION PREVENTS RENAL FIBROSIS IN CYCLOSPORINE NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Tyrosine Hydroxylase ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Control Group ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Type 2 Diabetic Patients ◽  
Inflammatory Infiltrates

Abstract Background and Aims Sodium glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, showed nephroprotection in type 2 diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is unclear whether the nephroprotective effects are present also in non-diabetic nephropathy. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, in cyclosporine nephropathy in the absence of diabetes. Method Ten days before the beginning and then during the entire experimental periods, low-salt diet (Teklad 7034) was administered to Sprague Dawley rats. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection; n=6) and CsA plus empagliflozin (Empa, 10 mg/kg /day, per os; n=6) were administered for 4 weeks. Control group was treated with placebo (n=6). Blood pressure was measured by plethysmographic method at the beginning and at the end of the experimental period. At the end of the protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and tyrosine hydroxylase expression, used as marker of symphatetic nerve activity. Results The rats treated with CsA showed a significant increase (p &lt;0.01) in blood pressure, which was slightly reduced by administration of empagliflozin. CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p &lt;0.05), renal inflammatory infiltrates (p &lt;0.05) and tyrosine hydroxylase expression (p &lt;0.01) as compared to the control rats. Treatment with empagliflozin reduced glomerular and tubulo-interstitial fibrosis (p &lt;0.05), inflammatory cell infiltration (p &lt;0.01) and tyrosine hydroxylase expression (p &lt;0.01), as compared to CsA-treated rats. Conclusion Empagliflozin administration showed protective effects on cyclosporine nephropathy, decreasing renal fibrosis, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that the nephroprotective role of empagliflozin could not be restricted only to diabetic nephropathy.

scholarly journals Subcellular trafficking of guanylyl cyclase/natriuretic peptide receptor-A with concurrent generation of intracellular cGMP

2015 ◽  
Vol 35 (5) ◽  
Author(s):  
Indra Mani ◽  
Renu Garg ◽  
Satyabha Tripathi ◽  
Kailash N. Pandey
Keyword(s):  
Blood Pressure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Fluid Volume ◽  
Natriuretic Peptide Receptor ◽  
Subcellular Trafficking ◽  
Peptide Receptor ◽  
Intracellular Cgmp ◽  
Natriuretic Peptide Receptor A

Atrial natriuretic peptide (ANP) modulates blood pressure and fluid volume by activation of natriuretic peptide receptor-A (NPRA). Immunofluorescence (IF) studies reveal that NPRA is internalized and redistributed into subcellular compartments with concurrent production of cGMP.

scholarly journals Increased Blood Pressure in α-Calcitonin Gene–Related Peptide/Calcitonin Gene Knockout Mice

Hypertension ◽  
2000 ◽  
Vol 35 (1) ◽  
pp. 470-475 ◽  
Author(s):  
Pandu R. R. Gangula ◽  
Huwai Zhao ◽  
Scott C. Supowit ◽  
Sunil J. Wimalawansa ◽  
Donald J. Dipette ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Gene Knockout Mice

scholarly journals FC 088DUAL BLOCKADE OF ENDOTHELIN A RECEPTOR (ETA) AND SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) TO PREVENT DIABETIC KIDNEY DISEASE PROGRESSION ON A TYPE 2 MURINE MODEL

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Ander Vergara Arana ◽  
Mireia Molina ◽  
Conxita Jacobs Cachá ◽  
Pamela Dominguez ◽  
Begoña Benito ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Kidney Disease ◽  
Urinary Albumin ◽  
Protective Effects ◽  
Mesangial Matrix ◽  
Sodium Glucose Cotransporter ◽  
Endothelin A Receptor ◽  
Matrix Expansion ◽  
Endothelin A

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and endothelin A receptor (ETA) antagonist have shown nephroprotective effects in diabetic kidney disease (DKD) through blood pressure and urinary albumin loss reduction. The protective impact and the pathways through which they exert this protection have not yet been elucidated. This study aimed to investigate the effects of the add-on therapy of SGLT2i and ETA antagonists on a type 2 diabetes murine model. Method 12 weeks-old db/db mice were treated for 8 weeks with different combinations of empagliflozin 10 mg/Kg/day (SGLT2i), atrasentan 7 mg/Kg/day (ETA antagonist) or ramipril 8 mg/Kg/day. A group of non-diabetic mice (db/m) was included as negative control. In vivo variables were recorded during treatment, including transdermal measured glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR). After treatment kidneys were preserved for histopathological studies. Results After 8 weeks of treatment empagliflozin decreased fasting blood glucose alone or in combination with atrasentan or ramipril (234.2 mg/dL mean reduction in three treated groups when compared to db/db). Ramipril decreased blood pressure (BP) in monotherapy or in add-on therapy. Empagliflozin or atrasentan alone did not have any effect on blood pressure, but combination of atrasentan and ramipril had a synergistic effect and reduced both systolic (9.0 mmHg, CI 95%: -16.3 to -1.1; P=0.028) and diastolic BP (11.9 mmHg, CI 95%: -17.7 to -3.1; P=0.005) when compared to ramipril alone. The combination of atrasentan and ramipril significantly reduced UACR (1002 ug/mg, CI 95%: -2312.0 to -32.4; P=0.043). Empagliflozin treatment alone or in combination also reduced UACR (686.0 ug/mg mean reduction in three treated groups), although this reduction was not statistically significant. In the kidney, empagliflozin in monotherapy or combination reduced glomerular mesangial matrix expansion (4.85% mean mesangial reduction in three treated groups). Treatments with atrasentan and ramipril also reduced measangial matrix expansion. Conclusion Both empagliflozin and atrasentan demonstrated possible beneficial effects in DKD by reducing BP, UACR, and mesangial matrix expansion. The add-on therapy did not show greater protective effects in the analysed variables. Further studies are needed to characterize these protective effects and pathways involved.

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