Abstract 196: Role of Collecting Duct Renin in Blood Pressure Regulation

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Sara Rees ◽  
Curt Sigmund ◽  
Donald E Kohan
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Dna Recombination ◽  
Plasma Renin ◽  
Blood Pressure Regulation ◽  
P System ◽  
Mrna Levels ◽  
Pressure Regulation ◽  
Renin Mrna ◽  
Exon 1

Recent studies propose that collecting duct (CD) renin is an important modulator of blood pressure regulation, especially in conditions such as angiotensin-II infused hypertension. We used gene targeting to generate a CD-specific renin knockout (KO) to assess if CD derived renin can regulate BP. Utilizing the Cre lox P system, exon 1 of the renin gene was ablated specifically in the CD. BP was recorded via telemetry and plasma and urine were collected in metabolic cages on normal, high and low Na diets. DNA recombination showed kidney specific recombination in KO mice. Compared to floxed mice, CD renin KO mice had 70 % lower medullary renin mRNA levels and 90% lower renin mRNA in micro-dissected cortical and inner medullary CD tubules. Urinary renin levels were significantly lower in the KO mice on normal and low Na diets (45% of floxed levels) but not with high Na intake. Plasma renin concentration was significantly higher in the KO mice on all three diets. While BP was similar between the two groups on all three diets, infusion of Ang-II delayed the increase in BP in the CD renin KO group for at least 4 days post-infusion. These findings suggest that CD renin likely plays a role in normal BP regulation (evidenced by an increase in PRC) and in response to AngII infusion.

scholarly journals Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension

2014 ◽  
Vol 307 (8) ◽  
pp. F931-F938 ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Sara Rees ◽  
Alfred Van Hoek ◽  
Curt D. Sigmund ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Ang Ii ◽  
Water Excretion ◽  
Protein Levels ◽  
Renin Gene ◽  
Induced Hypertension ◽  
Renin Mrna ◽  
Exon 1

The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure (BP) regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined BP and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO. Compared with controls, CD renin KO mice had 70% lower medullary renin mRNA and 90% lower renin mRNA in microdissected cortical CD. Urinary renin levels were significantly lower in KO mice (45% of control levels) while plasma renin concentration was significantly higher in KO mice (63% higher than controls) during normal-Na intake. While no observable differences were noted in BP between the two groups with varying Na intake, infusion of angiotensin II at 400 ng·kg−1·min−1 resulted in an attenuated hypertensive response in the KO mice (mean arterial pressure 111 ± 4 mmHg in KO vs. 128 ± 3 mmHg in controls). Urinary renin excretion and epithelial Na+ channel (ENaC) remained significantly lower in the KO mice following ANG II infusion compared with controls. Furthermore, membrane-associated ENaC protein levels were significantly lower in KO mice following ANG II infusion. These findings suggest that CD renin modulates BP in ANG II-infused hypertension and these effects are associated with changes in ENaC expression.

Role of Free Radicals and Angiotensin II in Blood Pressure Regulation in a Renal Model of Hypertension in Rat

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 696-696
Author(s):  
Anca D Dobrian ◽  
Russell L Prewitt
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Reduction ◽  
Plasma Renin ◽  
Treated Group ◽  
Blood Pressure Regulation ◽  
Kidney Cortex ◽  
Pressure Regulation ◽  
Wall Area ◽  
Link Type

P17 One kidney one clip (1K1C) or uninephrectomized controls were treated with either the SOD mimetic tempol (T) (0.5 mmol/kg/day), AT1 receptor inhibitor losartan (L) (50mM/kg/day), or both(L+T) (n=6/group), for 2 weeks. At the end of the study,systolic BP decreased on average by 21% in T- and 29% in L-treated compared to untreated 1K1C (217±4.4 mmHg) and was normalized in the L+T group (123.5±3.3 mmHg). Mean BP also decreased from 130±3.7 mmHg in 1K1C to 83±2.8mmHg in the L+T treated group. The differences were significant (p<0.003) as tested with Bonferroni multiple comparisons test. Also, aortic wall area was reduced by 18% in the L or T treated 1K1C and by 30% in the L+T rats, compared to 1K1C (0.548±0.03 mm2). Plasma renin activity was increased from 4.8±0.3 in 1K1C to 15.9±0.9 ng/ml/h in L - but not T- 1K1C. Superoxide generation by the isolated aortic rings assessed by lucigenin (25μM) chemiluminescence was significantly decreased by ∼40% in all L, T and L+T groups compared to 1K1C controls (1065±200 RLU/mg DNAx10 5 ). The nitrotyrosine ELISA assay in the kidney displayed a significant reduction from 59±13 ng/mg protein in 1K1C to 12.5±5 ng/mg protein in the L+T 1K1C rats. Western blotting for nNOS in the kidney cortex and medulla showed a protein increase in both fractions of 1K1C vs controls and was normalized by the L+T treatment. Collectively, data show a synergistic effect of L and T on the blood pressure reduction in 1K1C rats. The mechanism may involve the reduced superoxide production and decreased kidney nNOS expression in the treated animals. Also, the reduced nitrosylation of the proteins in the kidney might have an important effect on blood pressure regulation.

scholarly journals Creation of the 5-hydroxytryptamine receptor 7 knockout rat as a tool for cardiovascular research

2019 ◽  
Vol 51 (7) ◽  
pp. 290-301 ◽  
Author(s):  
Elena Y. Demireva ◽  
Huirong Xie ◽  
Emma D. Flood ◽  
Janice M. Thompson ◽  
Bridget M. Seitz ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vena Cava ◽  
Blood Pressure Regulation ◽  
Target Sequence ◽  
Pressure Regulation ◽  
Sprague Dawley ◽  
Cardiovascular Research ◽  
Exon 2 ◽  
Exon 1 ◽  
F2 Generation

Using CRISPR-Cas9 technology, we created a 5-HT7 receptor global knockout (KO) rat, on a Sprague-Dawley background, for use in cardiovascular physiology studies focused on blood pressure regulation. A stable line carrying indels in exons 1 and 2 of the rat Htr7 locus was established and validated. Surprisingly, 5-HT7 receptor mRNA was still present in the KO rat. However, extensive cDNA and genomic sequencing of KO tissues confirmed an 11 bp deletion in exon 1 and 4 bp deletion in exon 2. The exon 1 deletion resulted in a frameshifted mRNA sequence coding for a nonfunctional protein. While the Htr1B locus was a potential off-target for the guide RNAs designed for exon 2 of Htr7, there were no off-target sequence changes at this locus in the originating founder. When the F2 generation of KO was compared with wild-type (WT) counterparts, neither the male nor female KO rats were different in body size, fat weights, or mass of organs (kidney, heart, and brain) important to blood pressure. Females were smaller in mass than their counterpart males. Clinical measures of plasma from nonfasted rats revealed largely similar values, comparing WT and KO, of glucose, blood urea nitrogen, creatinine, phosphate, calcium, and albumin to name a few. Loss of a functional 5-HT7 receptor was validated by the complete loss of relaxation to the 5-HT1/7 receptor agonist 5-carboxamidotryptamine in the isolated abdominal vena cava. This newly created 5-HT7 receptor KO rat will be of use to investigate the importance of the 5-HT7 receptor in blood pressure regulation.

Comparison of renin-specific IgG and antibody fragments in studies of blood pressure regulation

1984 ◽  
Vol 246 (3) ◽  
pp. H404-H409 ◽  
Author(s):  
V. J. Dzau ◽  
R. I. Kopelman ◽  
A. C. Barger ◽  
E. Haber
Keyword(s):  
Blood Pressure ◽  
Plasma Renin Activity ◽  
Plasma Renin ◽  
Antibody Fragments ◽  
Blood Pressure Regulation ◽  
Renin Activity ◽  
Pressure Regulation ◽  
Systemic Pressure ◽  
Specific Igg ◽  
Mean Systemic Pressure

The use of antirenin antibody and its fragments as specific tools for the analysis of the role of renin in blood pressure regulation is assessed in this study. Specific immunoglobulin G (IgG) or its antibody fragments (Fab) raised against purified canine renal renin were employed. These agents had no effect on blood pressure in the sodium-replete unanesthetized dog but induced systemic vasodepressor response (16.4 +/- 2 mmHg mean pressure) and suppression of plasma renin activity in sodium-deplete animals. Renin-specific IgG or Fab restored mean systemic pressure of acute renovascular hypertensive dogs to normotensive levels (132 +/- 2 to 90 +/- 5 mmHg) associated with inhibition of plasma renin activity (11.2 +/- 2 to 1.4 +/- 0.7 ng angiotension I X ml-1 X h-1). A linear relationship was demonstrated between the reduction in mean systemic pressure and fall in plasma renin activity (r = 0.87, P less than 0.005). The onset of action of both agents occurred within minutes. However, the peak effect of Fab was observed within 1-2 min, while that of IgG was delayed by approximately 20 min. The duration of action of Fab was short lived (about 30 min) whereas that for IgG was prolonged (up to 24 h). The results demonstrate the usefulness of renin-specific IgG and Fab as tools in physiological studies.

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