scholarly journals ELABELA attenuates deoxycorticosterone acetate/salt-induced hypertension and renal injury by inhibition of NADPH oxidase/ROS/NLRP3 inflammasome pathway

2020 ◽  
Vol 11 (8) ◽  
Author(s):  
Zhida Chen ◽  
Chunying Wu ◽  
Yuting Liu ◽  
Haonan Li ◽  
Yeyan Zhu ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Nlrp3 Inflammasome ◽  
Renal Injury ◽  
Mrna Level ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Receptor Protein ◽  
Deoxycorticosterone Acetate ◽  
Renal Tubular Cells ◽  
Induced Hypertension ◽  
Apelin Receptor

Abstract ELABELA (ELA), a 32-residue hormone peptide abundantly expressed in adult kidneys, has been identified as a novel endogenous ligand for APJ/Apelin receptor. The aim of this study was to investigate the role of ELA in deoxycorticosterone acetate (DOCA)/salt-induced hypertension and further explore the underlying mechanism. In DOCA/salt-treated rats, the mRNA level of ELA greatly decreased in the renal medulla. Next, overexpression of ELA in the kidney was found to attenuate DOCA/salt-induced hypertension and renal injury, including lower blood pressure, reversed glomerular morphological damage, decreased blood urea nitrogen (BUN), and blocked the accumulation of fibrotic markers. Mechanistically, ELA overexpression inhibited renal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subsequent reactive oxygen species (ROS) production, thus resulted in the blockade of formation and activation of Nod-like receptor protein 3 (NLRP3) inflammasome. The inhibitory effects of ELA on Aldosterone-stimulated NADPH oxidase/ROS/NLRP3 inflammasome pathway were confirmed in the human renal tubular cells. Furthermore, our in vivo and in vitro results showed that the deficiency of the apelin receptor APJ did not influence the antihypertensive effect and blockage to NADPH oxidase/ROS/NLRP3 pathway of ELA. Moreover, in heterozygous ELA knockout mice (ELA+/−), the ELA deficiency remarkably accelerated the onset of DOCA/salt-induced hypertension. Our data demonstrate that ELA prevents DOCA/salt-induced hypertension by inhibiting NADPH oxidase/ROS/NLRP3 pathway in the kidney, which is APJ independent. Pharmacological targeting of ELA may serve as a novel therapeutic strategy for the treatment of hypertensive kidney disease.

Abstract 254: Inflammasome Activity Is Essential For Deoxycorticosterone Acetate/salt-induced Hypertension In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Shalini M Krishnan ◽  
Christopher G Sobey ◽  
Barbara Kemp-Harper ◽  
Christopher T Chan ◽  
Henry Diep ◽  
...  
Keyword(s):  
Drinking Water ◽  
Receptor Protein ◽  
Salt Treatment ◽  
Deoxycorticosterone Acetate ◽  
Renal Inflammation ◽  
Protein Levels ◽  
Caspase 1 ◽  
Induced Hypertension ◽  
The Impact ◽  
Inflammasome Activity

Inflammasomes are signalling complexes comprised of a NOD-like receptor protein (NLRP), an adapter protein (ASC) and caspase-1. Inflammasomes detect host-derived danger signals and induce inflammation via activation of caspase-1, which in turn cleaves the cytokines pro-interleukin(IL)-1β and pro-IL-18 into their active, pro-inflammatory forms. Hypertension is associated with chronic renal inflammation, but the role of the inflammasome in this process is not known. Hence, we tested whether deoxycorticosterone acetate (DOCA)/salt-induced hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and assessed the impact of inhibition of inflammasome activity on blood pressure (BP) and markers of renal inflammation and fibrosis. Male C57BL6/J (wild type) and ASC -/- mice were uninephrectomised, implanted with a DOCA pellet (2.4 mg/d, 21 d, s.c. ) and had their drinking water replaced with 1% saline (1K/DOCA/salt). Control mice had a kidney removed but received a placebo pellet and normal drinking water. 1K/DOCA/salt-treated mice had elevated systolic BP (146±4 mmHg) compared to control mice (115±2 mmHg; n=13-16; P<0.05). 1K/DOCA/salt-induced hypertension was associated with increased renal mRNA expression (fold-change vs control; n=7-9; P<0.05) of inflammasome subunits NLRP3 (2.3±0.2), ASC (2.8±0.6) and pro-caspase-1 (2.6±0.5), and the cytokine, pro-IL-1 (4.0±0.8). Moreover, protein levels of cleaved (active) caspase-1 and IL-1 were increased by 1.6±0.2- and 2.1±0.3-fold, respectively in kidneys of 1K/DOCA/salt vs control mice (n=6; P<0.05). ASC -/- mice, which lack an active inflammasome complex, displayed blunted hypertensive responses to 1K/DOCA/salt-treatment (140±3 mmHg) compared to wild types (155±8 mmHg; n=8-9; P<0.05). ASC -/- mice were also protected from 1K/DOCA/salt-induced increases in renal expression of the inflammatory genes IL-6, IL-17a, CCL2, ICAM-1 and VCAM-1, and accumulation of collagen. Thus, renal inflammation, fibrosis and elevated BP in response to 1K/DOCA/salt-treatment are critically dependent on inflammasome activity, highlighting this signalling complex and its cytokine products as potential therapeutic targets to treat hypertension.

scholarly journals Platelet Inhibition Prevents NLRP3 Inflammasome Activation and Sepsis-Induced Kidney Injury

2021 ◽  
Vol 22 (19) ◽  
pp. 10330
Author(s):  
Marivee Borges-Rodriguez ◽  
Corbin A. Shields ◽  
Olivia K. Travis ◽  
Robert W. Tramel ◽  
Cedar H. Baik ◽  
...  
Keyword(s):  
Renal Function ◽  
Platelet Activation ◽  
Nlrp3 Inflammasome ◽  
Renal Injury ◽  
Cecal Ligation ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Glomerular Injury ◽  
Activated Platelets ◽  
Nlrp3 Inflammasome Activation

Platelets, cellular mediators of thrombosis, are activated during sepsis and are increasingly recognized as mediators of the immune response. Platelet activation is significantly increased in sepsis patients compared to ICU control patients. Despite this correlation, the role of activated platelets in contributing to sepsis pathophysiology remains unclear. We previously demonstrated NOD-like receptor protein 3 inflammasome (NLRP3) inflammasome activation in sepsis-induced platelets from cecal-ligation puncture (CLP) rats. Activated platelets were associated with increased pulmonary edema and glomerular injury in CLP vs. SHAM controls. In this study, we investigated whether inhibition of platelet activation would attenuate NLRP3 activation and renal and pulmonary injury in response to CLP. CLP was performed in male and female Sprague Dawley (SD) rats (n = 10/group) to induce abdominal sepsis and SHAM rats served as controls. A subset of CLP animals was treated with Clopidogrel (10 mg/kg/day, CLP + CLOP) to inhibit platelet activation. At 72 h post-CLP, platelet activation and NLRP3 inflammasome assembly were evaluated, IL-1β and IL-18 were measured in plasma, and tissues, renal and pulmonary pathology, and renal function were assessed. Activated platelets were 7.8 ± 3.6% in Sham, 22 ± 6% in CLP and significantly decreased to 14.5 ± 0.6% in CLP + CLOP (n = 8–10/group, p < 0.05). NLRP3 inflammasome assembly was inhibited in platelets of CLP + CLOP animals vs. CLP. Significant increases in plasma and kidney IL-1β and IL-18 in response to CLP were decreased with Clopidogrel treatment. Renal injury, but not lung histology or renal function was improved in CLP + CLOP vs. CLP. These data provide evidence that activated platelets may contribute to sepsis-induced renal injury, possibly via NLRP3 activation in platelets. Platelets may be a therapeutic target to decrease renal injury in septic patients.

scholarly journals Micheliolide Attenuates Lipopolysaccharide-Induced Inflammation by Modulating the mROS/NF-κB/NLRP3 Axis in Renal Tubular Epithelial Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xianghong Lei ◽  
Shuting Li ◽  
Congwei Luo ◽  
Yuxian Wang ◽  
Yanxia Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Tubular Epithelial Cells ◽  
Renal Inflammation ◽  
Renal Tubular Cells ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory ◽  
Renal Tubular

Chronic kidney disease is a common disease closely related to renal tubular inflammation and oxidative stress, and no effective treatment is available. Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important factor in renal inflammation, but the mechanism remains unclear. Micheliolide (MCL), which is derived from parthenolide, is a new compound with antioxidative and anti-inflammatory effects and has multiple roles in tumors and inflammatory diseases. In this study, we investigated the effect of MCL on lipopolysaccharide- (LPS-) induced inflammation in renal tubular cells and the related mechanism. We found that MCL significantly suppressed the LPS-induced NF-κB signaling and inflammatory expression of cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in a rat renal proximal tubular cell line (NRK-52E). MCL also prevented LPS- and adenosine triphosphate-induced NLRP3 inflammasome activation in vitro, as evidenced by the inhibition of NLRP3 expression, caspase-1 cleavage, and interleukin-1β and interleukin-18 maturation and secretion. Additionally, MCL inhibited the reduction of mitochondrial membrane potential and decreases the release of reactive oxygen species (ROS). Moreover, MCL can prevent NLRP3 inflammasome activation induced by rotenone, a well-known mitochondrial ROS (mROS) agonist, indicating that the mechanism of MCL’s anti-inflammatory effect may be closely related to the mROS. In conclusion, our study indicates that MCL can inhibit LPS-induced renal inflammation through suppressing the mROS/NF-κB/NLRP3 axis in tubular epithelial cells.

Role of gp91phox-containing NADPH oxidase in the deoxycorticosterone acetate-salt-induced hypertension

2006 ◽  
Vol 552 (1-3) ◽  
pp. 131-134 ◽  
Author(s):  
Aya Fujii ◽  
Daisuke Nakano ◽  
Miyuki Katsuragi ◽  
Mamoru Ohkita ◽  
Masanori Takaoka ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Deoxycorticosterone Acetate ◽  
Acetate Salt ◽  
Induced Hypertension

scholarly journals Deficiency of the Interleukin 17/23 Axis Accelerates Renal Injury in Mice With Deoxycorticosterone Acetate+Angiotensin II–Induced Hypertension

Hypertension ◽  
2014 ◽  
Vol 63 (3) ◽  
pp. 565-571 ◽  
Author(s):  
Christian F. Krebs ◽  
Sascha Lange ◽  
Gianina Niemann ◽  
Alva Rosendahl ◽  
Alexander Lehners ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Interleukin 17 ◽  
Deoxycorticosterone Acetate ◽  
Induced Hypertension

scholarly journals The Role of P2X7 Purinergic Receptors in the Renal Inflammation Associated with Angiotensin II-Induced Hypertension

2020 ◽  
Vol 21 (11) ◽  
pp. 4041 ◽  
Author(s):  
Rocio Bautista-Pérez ◽  
Oscar Pérez-Méndez ◽  
Agustina Cano-Martínez ◽  
Ursino Pacheco ◽  
José Santamaría ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nlrp3 Inflammasome ◽  
Purinergic Receptors ◽  
Inflammatory Cells ◽  
P2x7 Receptors ◽  
Renal Vasoconstriction ◽  
Renal Tubular Cells ◽  
Induced Hypertension ◽  
Glomerular Hemodynamics ◽  
Tubulointerstitial Inflammation

Purinergic receptors play a central role in the renal pathophysiology of angiotensin II-induced hypertension, since elevated ATP chronically activates P2X7 receptors in this model. The changes induced by the P2X antagonist Brilliant blue G (BBG) in glomerular hemodynamics and in tubulointerstitial inflammation resulting from angiotensin II infusion were studied. Rats received angiotensin II (435 ng kg−1 min−1, 2 weeks) alone or in combination with BBG (50 mg/kg/day intraperitoneally). BBG did not modify hypertension (214.5 ± 1.4 vs. 212.7 ± 0.5 mmHg), but restored to near normal values afferent (7.03 ± 1.00 to 2.97 ± 0.27 dyn.s.cm−5) and efferent (2.62 ± 0.03 to 1.29 ± 0.09 dyn.s.cm−5) arteriolar resistances, glomerular plasma flow (79.23 ± 3.15 to 134.30 ± 1.11 nL/min), ultrafiltration coefficient (0.020 ± 0.002 to 0.036 ± 0.003 nL/min/mmHg) and single nephron glomerular filtration rate (22.28 ± 2.04 to 34.46 ± 1.54 nL/min). Angiotensin II induced overexpression of P2X7 receptors in renal tubular cells and in infiltrating T and B lymphocytes and macrophages. All inflammatory cells were increased by angiotensin II infusion and reduced by 20% to 50% (p < 0.05) by BBG administration. Increased IL-2, IL-6, TNFα, IL-1β, IL-18 and overexpression of NLRP3 inflammasome were induced by angiotensin II and suppressed by BBG. These studies suggest that P2X7 receptor-mediated renal vasoconstriction, tubulointerstitial inflammation and activation of NLRP3 inflammasome are associated with angiotensin II-induced hypertension.

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