Abstract P002: Soluble (pro)renin Receptor Contributes To Angiotensin II-Induced Hypertension In Mice

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Ye Feng ◽  
Fei Wang ◽  
Kexin Peng ◽  
Yanting Chen ◽  
Renfei Luo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Short Circuit Current ◽  
Mutant Mice ◽  
Induced Hypertension ◽  
Renin Level ◽  
Intrarenal Ras

Activation of (pro)renin receptor (PRR) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during angiotensin II (AngII) infusion. Soluble PRR (sPRR), the extracellular domain of PRR, is generated by multiple proteases including furin or ADAM19, and recently site-1 protease (S1P). The goal of the present study was to test the role of S1P-derived sPRR mediated AngII-induced hypertension. F1 B6129SF1/J mice were infused for 6 days with control (CTR) or AngII at 300 ng/kg/day alone or in combination with S1P inhibitor PF-429242 (PF) and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated AngII-induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histadine-tagged sPRR termed as sPRR-His. Mutagenesis of overlapping recognition site for S1P and furin in PRR for was generated in mice by CRISPR strategy (termed as mutant mice). Mutant mice were fertile and developed normally with a 50% reduction plasma sPRR. These mice exhibited blunted hypertensive response to AngII infusion accompanied with suppressed intrarenal renin levels. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mpkCCD cells exposed for 24 h to AngII, AngII + PF, or AngII + PF + sPRR-His. AngII-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that sPRR derived from S1P or in combination with furin mediates AngII-induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

scholarly journals Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II–Induced Hypertension in Mice

Hypertension ◽  
2020 ◽  
Author(s):  
Ye Feng ◽  
Kexin Peng ◽  
Renfei Luo ◽  
Fei Wang ◽  
Tianxin Yang
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Collecting Duct ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Short Circuit Current ◽  
Duct Cell ◽  
Ang Ii ◽  
Cortical Collecting Duct ◽  
Induced Hypertension

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

scholarly journals Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

2019 ◽  
Vol 51 (4) ◽  
pp. 97-108 ◽  
Author(s):  
Xiao C. Li ◽  
Xiaowen Zheng ◽  
Xu Chen ◽  
Chunling Zhao ◽  
Dongmin Zhu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Blood Pressure Homeostasis ◽  
Induced Hypertension ◽  
Basal Blood Pressure

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

Abstract 101: Cardiac Deleterious Role of Galectin-3 in Chronic Angiotensin-II Induced Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Germán E González ◽  
Nour-Eddine Rhaleb ◽  
Xiao- P Yang ◽  
Oscar A Carretero
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Carbohydrate Binding ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Galectin 3

We previously described that chronic infusion with Angiotensin II (Ang II) increases cardiac Galectin-3 (Gal-3) expression, a carbohydrate-binding lectin present on macrophages. Also, Gal-3 was proposed to be a powerful predictor for mortality in patients with heart failure. Nevertheless, the role of Gal-3 in the pathogenesis of end organ damage (EOD) in hypertension is unknown. Here, we hypothesized that in Ang II-induced hypertension, genetic deletion of Gal-3 prevents innate immunity, EOD, and left ventricular (LV) dysfunction. Male C57 and Gal-3 KO mice were infused with vehicle (V) or Ang II (90 ng/min; s.c.) for 8 weeks and divided into: 1) C57 + V; 2) Gal-3 KO + V; 3) C57 + Ang II and 4) Gal-3 KO + Ang II. Systolic blood pressure (SBP) was measured by plestimography weekly. At 8 week, we evaluated 1) LV ejection fraction (EF) by echocardiography; 2) cardiac hypertrophy by LV weight/tibia length; 3) cardiac fibrosis by picrosirius red staining; 4) infiltrated macrophages by CD68+ staining; 5) ICAM-1 protein expression by Western blot; and 6) serum interleukin (IL)-6 by ELISA. We found that despite a similar increase in SBP and LV hypertrophy in both strains on Ang II, Gal-3 KO mice had better reserved EF and decreased inflammatory and fibrotic responses (see Table). Results: (MEAN ± SEM at 8 w) *p<0.05 C57+Ang II and Gal-3 KO+Ang II vs C57+V; ‡ p<0.05 Gal-3 KO+Ang II vs C57+Ang II. Conclusion: In Ang II-induced hypertension, deletion of Gal-3 prevents EOD and LV systolic dysfunction without altering blood pressure and LV hypertrophy. This study indicates that the deleterious effects of Ang II could be in part mediated by Gal-3, which enhanced inflammation and fibrosis.

Abstract P229: Site-1 Protease-derived Soluble (pro) Renin Receptor Mediates Aldosterone-induced Enac Activation In The Collecting Duct

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Fei Wang ◽  
Renfei Luo ◽  
KEXIN PENG ◽  
Peng Wu ◽  
Xiyang Liu ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Fold Increase ◽  
Short Circuit Current ◽  
Vehicle Group ◽  
Α Subunit ◽  
Collecting Duct Cells

We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na + channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), generated by site-1 protease (S1P), a newly identified PRR cleavage protease, in ENaC regulation, and further tested its relevance to Aldo signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM for 24 h induced a significant increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique ( I eq : 7.5 ± 0.7 μA/cm 2 in sPRR group vs. 3.5 ± 0.5 μA/cm 2 in vehicle group, n = 6, p < 0.01) . In primary cultured rat IMCD cells, the same sPRR-His treatment induced a 1.7 fold increase in protein expression of the α-subunit but not β- or γ-subunit of ENaC, in parallel with upregulation of mRNA expression as well as promoter activity of the α-subunit. The upregulation of α-ENaC transcription depended on β-catenin signaling. Consistent results obtained by epithelial volt ohmmeter measurement of equivalent current and Using chamber determination of short-circuit current showed that Aldo-induced ENaC activity was almost completely abolished by PF-429242 (PF), a S1P inhibitor, and the response was restored by supplement of sPRR-His ( I eq : 7.2 ± 0.7 μA/cm 2 in Aldo group vs. 5.0 ± 0.3 μA/cm 2 in Aldo/PF group vs. 6.8 ± 0.3 μA/cm 2 in Aldo/PF/sPRR-His group, n = 5, p < 0.05). Medium sPRR was elevated by Aldo and inhibited by PF. Male C57BL/6 mice were pretreated with PF (30 mg/kg/day) or vehicle via minipump, followed by 3 days of aldosterone (0.2 mg/kg/day via a second minipump). Amiloride-sensitive Na+ current in freshly isolated CCD as measured by using patch clamp lower in Aldo + PF group than in Aldo group. Together, these results support an essential role of S1P-derived sPRR in mediating Aldo-induced ENaC activation.

Role of collecting duct renin in blood pressure regulation

2013 ◽  
Vol 305 (2) ◽  
pp. R92-R94 ◽  
Author(s):  
Nirupama Ramkumar ◽  
Donald E. Kohan
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Collecting Duct ◽  
Direct Interaction ◽  
Pressure Regulation ◽  
Increase Blood Pressure ◽  
Distal Nephron ◽  
At1 Receptors ◽  
Induced Hypertension

Numerous studies indicate that renin is synthesized and secreted by the collecting duct (CD). CD-derived renin may act directly on intercalated and/or principal cells through direct interaction with prorenin receptors and/or through cleavage of proximal tubule-derived angiotensinogen to ultimately produce angiotensin II and activate AT1 receptors. Preliminary studies suggest that the net effect of CD renin would be to increase distal nephron salt reabsorption and increase blood pressure. CD renin production is markedly increased in diabetes and angiotensin II-induced hypertension, suggesting that this system may exert pathophysiological effects. In this brief review, we summarize the current literature on synthesis and regulation of CD renin and consider potential mechanisms by which it regulates blood pressure.

Abstract 15061: Essential Hypertension is Linked to Acetylation of Mitochondrial Superoxide Dismutase and Deacetylation Mimetic Mutation of Lysine 68 to Arginine Protects From Oxidative Stress and Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anna Dikalova ◽  
Liliya Tkachuk ◽  
Marcos G Lopez ◽  
Frederic T Billings ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Superoxide Dismutase ◽  
Essential Hypertension ◽  
Angiotensin Ii ◽  
Wild Type ◽  
Mitochondrial Superoxide ◽  
Induced Hypertension ◽  
Lysine Residues

Almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. We found that hypertension is associated with inactivation of key mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to acetylation of lysine residues at the catalytic center. The role of specific SOD2 lysine residues in hypertension, however, has not been defined. Hypothesis: We proposed that inactivation of key intrinsic antioxidant, SOD2, in hypertension is linked to acetylation of Lysine 68, and mutation of K68 to Arginine mimics SOD2 deacetylation, inhibits vascular oxidative stress and attenuates angiotensin II-induced hypertension. To test this hypothesis, we have investigated SOD2 acetylation in arterioles from patients with essential hypertension and developed a new deacetylation mimic SOD2 mutant K68R mice (SOD2-K68R). Western blot of arterioles isolated from human mediastinal fat showed 3-fold increase in SOD2 acetylation in hypertensive patients compared with normotensive subjects while SOD2 levels were not affected. To define the functional significance of K68 acetylation we performed studies in vivo in SOD2-K68R mice using angiotensin II model of vascular dysfunction and hypertension. Angiotensin II infusion in wild-type C57Bl/6J mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. Mutation of Lysine 68 to Arginine in SOD2-K68R mice completely prevented the increase in mitochondrial superoxide and significantly attenuated the angiotensin II induced hypertension (135 mm Hg). Angiotensin II and TNFα co-operatively induce SOD2 acetylation and hypertension. Treatment of wild-type aortas with angiotensin II and TNFα in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. Conclusions: These data support an important role of SOD2-K68 acetylation in hypertension and targeting Sirt3-mediated deacetylation of SOD2 may have therapeutic potential.

Abstract P080: Mutation Of Lysine 68 To Arginine Mimics Deacetylation Of Mitochondrial Superoxide Dismutase, Protects From Vascular Oxidative Stress And Attenuates Angiotensin II-Induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Anna Dikalova ◽  
Liliya Tkachuk ◽  
Marcos G Lopez ◽  
Frederic T Billings ◽  
Sergey I Dikalov
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Superoxide Dismutase ◽  
Angiotensin Ii ◽  
Wild Type ◽  
Mitochondrial Superoxide ◽  
Induced Hypertension ◽  
Lysine Residues ◽  
Vascular Oxidative Stress

By recent guidelines, almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. We found that hypertension is associated with inactivation of key mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to acetylation of lysine residues at the catalytic center. The role of specific SOD2 lysine residues in hypertension, however, has not been defined. We proposed that inactivation of key intrinsic antioxidant, SOD2, in hypertension is linked to acetylation of Lysine 68, and mutation of K68 to Arginine mimics SOD2 deacetylation, inhibits vascular oxidative stress and attenuates angiotensin II-induced hypertension. To test this hypothesis, we have investigated SOD2 acetylation in arterioles from patients with essential hypertension and developed a new deacetylation mimic SOD2 mutant K68R mice (SOD2-K68R). Western blot analysis of arterioles isolated from human mediastinal fat showed 3-fold increase in SOD2 acetylation in hypertensive patients compared with normotensive subjects while SOD2 levels were not affected. To define the functional significance of K68 acetylation we performed studies in vivo in SOD2-K68R mice using angiotensin II model of vascular dysfunction and hypertension. Angiotensin II infusion in wild-type C57Bl/6J mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. Mutation of Lysine 68 to Arginine in SOD2-K68R mice completely prevented the increase in mitochondrial superoxide and significantly attenuated the angiotensin II induced hypertension (135 mm Hg). Angiotensin II and TNFα co-operatively induce SOD2 acetylation and hypertension. Treatment of wild-type aortas with angiotensin II and TNFα in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. These data support an important role of SOD2-K68 acetylation in hypertension, and strategies to reduce mitochondrial acetylation may have therapeutic potential.

scholarly journals The role of HCO3– in propionate-induced anion secretion across rat caecal epithelium

2021 ◽  
Author(s):  
Jasmin Ballout ◽  
Martin Diener
Keyword(s):  
Regional Differences ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Short Circuit Current ◽  
Short Chain Fatty Acids ◽  
Microbial Fermentation ◽  
Anion Secretion ◽  
Ionic Mechanisms ◽  
Stilbene Derivatives

AbstractPropionate, a metabolite from the microbial fermentation of carbohydrates, evokes a release of epithelial acetylcholine in rat caecum resulting in an increase of short-circuit current (Isc) in Ussing chamber experiments. The present experiments were performed in order to characterize the ionic mechanisms underlying this response which has been thought to be due to Cl− secretion. As there are regional differences within the caecal epithelium, the experiments were conducted at oral and aboral rat corpus caeci. In both caecal segments, the propionate-induced Isc (IProp) was inhibited by > 85%, when the experiments were performed either in nominally Cl−- or nominally HCO3−-free buffer. In the case of Cl−, the dependency was restricted to the presence of Cl− in the serosal bath. Bumetanide, a blocker of the Na+-K+-2Cl−-cotransporter, only numerically reduced IProp suggesting that a large part of this current must be carried by an ion other than Cl−. In the aboral caecum, IProp was significantly inhibited by mucosally administered stilbene derivatives (SITS, DIDS, DNDS), which block anion exchangers. Serosal Na+-free buffer reduced IProp significantly in the oral (and numerically also in aboral) corpus caeci. RT-PCR experiments revealed the expression of several forms of Na+-dependent HCO3−-cotransporters in caecum, which might underlie the observed Na+ dependency. These results suggest that propionate sensing in caecum is coupled to HCO3– secretion, which functionally would stabilize luminal pH when the microbial fermentation leads to an increase in the concentration of short-chain fatty acids in the caecal lumen.

scholarly journals Influence of prostaglandins on unidirectional zinc fluxes across the small intestine of the rat

1988 ◽  
Vol 59 (3) ◽  
pp. 417-428 ◽  
Author(s):  
Moon K. Song ◽  
David B. N. Lee ◽  
Nabeel F. Adham
Keyword(s):  
Short Circuit ◽  
Ussing Chamber ◽  
Short Circuit Current ◽  
Mucosal Cell ◽  
Flux Rate ◽  
Serosal Side ◽  
Uptake Capacity ◽  
Bathing Medium ◽  
Mucosal Side

1. The regulatory role of prostaglandins (PGs) E2 and F2a on the zinc transport rate across the jejunal segments of rats was examined by employing the Ussing chamber technique. The Zn flux rate from mucosa to serosa across jejunal segments (Jms) was 5·24 (SE 1·54) nmol/h per cm2 (n 48) and that from serosa to mucosa (Jsm) was 15·16 (SE 2·38) nmol/h per cm2 (n 48) when both sides of the segment were bathed with Ringer's bicarbonate solution containing 0·5 mM-zinc chloride and 3 mM-L-histidine.2. When 5·0 or 50 μM of either PGE2 or PGF2α were added to the serosal side of the tissue, Jsm generally decreased and Jms generally increased, compared with controls. On the other hand, when PGE2 or PGF2α was added to the mucosal side of the tissue, Jms either did not change or increased while Jsm had a tendency to decrease.3. The Zn uptake capacity of tissue increased significantly when PG was added to the serosal side of the tissuebathing medium, but not when PG was added to the mucosal side. The uptake capacity of mucosal Zn by jejunal segments was approximately twice that of serosal Zn.4. When PG was included in the tissue-bathing medium, the short-circuit current, potential difference and conductance between the mucosa- and serosa-bathing media generally decreased.5. These results suggest that (a) PGs influence Zn flux rate not by chelating Zn and carrying it across the mucosal cell membrane but by interacting with the cytosolic components, (b) it is the serosal PGs which control the Zn flux rate and (c) PGs play a part in triggering a transduction mechanism in the intestinal Zn transport process.

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