scholarly journals Pressure-natriuresis and -diuresis in transgenic rats harboring both human renin and human angiotensinogen genes.

1998 ◽  
Vol 9 (12) ◽  
pp. 2212-2222
Author(s):  
B Dehmel ◽  
E Mervaala ◽  
A Lippoldt ◽  
V Gross ◽  
J Bohlender ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renin Angiotensin System ◽  
Renal Perfusion ◽  
Transgenic Rat ◽  
Water Excretion ◽  
Excretory Function ◽  
Human Renin ◽  
Renin Gene ◽  
Renin Mrna ◽  
Pressure Natriuresis

The hypertensive double transgenic rat harboring both the human renin and human angiotensinogen genes (dTGR) offers a unique opportunity to study the human renin-angiotensin system in an experimental animal model. Since nothing is known about the control of sodium and water excretion in these rats, this study was performed to compare pressure-natriuresis relationships in hypertensive dTGR and normotensive control rats harboring only the human renin gene (hREN), in order to determine how the pressure-natriuresis relationship is reset in hypertensive dTGR. To differentiate between extrinsic and intrinsic renal mechanisms, experiments were performed with and without renal denervation, and with and without infusions of vasopressin, norepinephrine, 17-OH-corticosterone, and aldosterone. Human and rat angiotensinogen and renin mRNA expression were also determined. In hREN without controlled renal function, urine flow and sodium excretion increased from 13 to 169 microl/min per g kidney wet weight (kwt) and from 1 to 30 micromol/min per g kwt, respectively, as renal perfusion pressure was increased from 67 to 135 mmHg. Renal blood flow (RBF) and GFR ranged between 3 to 7 and 0.9 to 1.5 ml/min per g kwt. In dTGR, pressure-natriuresis-diuresis relationships were shifted approximately 40 mmHg rightward. RBF was lower in dTGR than in hREN; GFR was not different. In dTGR with neurohormonal factors controlled, RBF was decreased and pressure-natriuresis-diuresis curves were not different compared to dTGR curves without these interventions. By light microscopy, the kidneys of these 6-wk-old dTGR and hREN rats were normal and indistinguishable. Both human and rat renin and angiotensinogen mRNA were expressed in the kidneys of dTGR. The two renin mRNA were decreased in dTGR, indicating a physiologic downregulation of renin gene expression by high BP. It is concluded that the renal pressure-natriuresis mechanism is reset toward higher pressure levels in dTGR and participates in the maintenance of hypertension. The reduced excretory function in dTGR depends on hREN and human angiotensinogen gene expression and is intrinsic to the kidney as opposed to extrarenal regulators.

JG cell expression and partial regulation of a human renin genomic transgene driven by a minimal renin promoter

1999 ◽  
Vol 277 (4) ◽  
pp. F634-F642 ◽  
Author(s):  
Patrick L. Sinn ◽  
Xiaoji Zhang ◽  
Curt D. Sigmund
Keyword(s):  
Gene Expression ◽  
Systemic Circulation ◽  
Proximal Promoter ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Specific Expression ◽  
Renin Synthesis ◽  
Human Renin ◽  
Renin Gene ◽  
Renin Mrna ◽  
Cell Expression

In the kidney, renin gene expression is exquisitely localized to the juxtaglomerular (JG) cells lining the afferent arteriole, having the capacity to regulate renin synthesis in response to a variety of physiological cues. We investigated human renin gene expression in transgenic mice containing a genomic construct driven by 149 bp of its proximal promoter to elucidate whether this was sufficient to confer JG-specific expression. Whereas human renin mRNA was permissively expressed in most tissues, the transgene was expressed mainly in JG cells in the kidney. Active human renin and human prorenin were found in the systemic circulation at levels consistent with previous transgenic models. Remarkably, two lines displayed an appropriate upregulation of transgene mRNA in response to angiotensin-converting enzyme inhibition, and two lines exhibited a downregulation of transgene mRNA in response to subpressor and pressor doses of ANG II. Our results suggest that 149 bp of the human renin proximal promoter, in a context of a genomic construct, are sufficient to confer human renin expression in renal JG cells and at least some aspects of appropriate regulation.

A Widespread Abnormality of Renin Gene Expression in the Spontaneously Hypertensive Rat: Modulation in Some Tissues with the Development of Hypertension

1989 ◽  
Vol 77 (6) ◽  
pp. 629-636 ◽  
Author(s):  
Nilesh J. Samani ◽  
John D. Swales ◽  
William J. Brammar
Keyword(s):  
Gene Expression ◽  
Messenger Rna ◽  
Renin Angiotensin System ◽  
Mrna Levels ◽  
Angiotensin System ◽  
Spontaneously Hypertensive ◽  
Renin Angiotensin ◽  
Renin Gene ◽  
Renin Mrna ◽  
Ribonuclease Protection

1. Renin messenger RNA (mRNA) levels were compared in the kidneys, livers, brains, adrenals, aortae and hearts of spontaneously hypertensive (SHR) and Wistar—Kyoto (WKY) rats at 5 and 12 weeks of age using a ribonuclease-protection technique 2. Relative levels of renin mRNA were increased in the kidney, liver, brain, adrenal and heart of the young SHR compared with the WKY. In the aorta, levels were similar in the two strains at 5 weeks 3. In 12-week-old animals, while increased levels persisted in the liver, brain and adrenal of the SHR, the level in the kidney was now the same in the two strains and the levels in the heart and aorta were lower in the SHR compared with the WKY 4. Renin mRNA levels in the kidneys of SHR and WKY were also compared by Northern blotting and confirmed the observations made with the ribonuclease-protection technique 5. The findings indicate a widespread abnormality of renin gene expression in the SHR which is modulated in some tissues by the development of hypertension 6. While the mechanism(s) for the abnormality remains to be determined, the increased renin mRNA levels in the SHR in several tissues concerned with blood pressure regulation suggests an important role for the renin-angiotensin system in the development and maintenance of hypertension 7. However, the finding of increased renin mRNA in the liver also suggests abnormalities in other, as yet unknown, functions of the renin—angiotensin system in the SHR.

Hypertensive retinopathy in a transgenic angiotensin-based model

2016 ◽  
Vol 130 (13) ◽  
pp. 1075-1088 ◽  
Author(s):  
Nadine Reichhart ◽  
Nadine Haase ◽  
Sergio Crespo-Garcia ◽  
Sergej Skosyrski ◽  
Christina Herrspiegel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ganglion Cells ◽  
Renin Angiotensin System ◽  
Retinal Disease ◽  
Fluorescence Angiography ◽  
Peripheral Retina ◽  
Transgenic Rat ◽  
Hypertensive Retinopathy ◽  
Sprague Dawley ◽  
Blood Retinal Barrier

Severe hypertension destroys eyesight. The RAS (renin–angiotensin system) may contribute to this. This study relied on an established angiotensin, AngII (angiotensin II)-elevated dTGR (double-transgenic rat) model and same-background SD (Sprague–Dawley) rat controls. In dTGRs, plasma levels of AngII were increased. We determined the general retinal phenotype and observed degeneration of ganglion cells that we defined as vascular degeneration. We also inspected relevant gene expression and lastly observed alterations in the outer blood–retinal barrier. We found that both scotopic a-wave and b-wave as well as oscillatory potential amplitude were significantly decreased in dTGRs, compared with SD rat controls. However, the b/a-wave ratio remained unchanged. Fluorescence angiography of the peripheral retina indicated that exudates, or fluorescein leakage, from peripheral vessels were increased in dTGRs compared with controls. Immunohistological analysis of blood vessels in retina whole-mount preparations showed structural alterations in the retina of dTGRs. We then determined the general retinal phenotype. We observed the degeneration of ganglion cells, defined vascular degenerations and finally found differential expression of RAS-related genes and angiogenic genes. We found the expression of both human angiotensinogen and human renin in the hypertensive retina. Although the renin gene expression was not altered, the AngII levels in the retina were increased 4-fold in the dTGR retina compared with that in SD rats, a finding with mechanistic implications. We suggest that alterations in the outer blood–retinal barrier could foster an area of visual-related research based on our findings. Finally, we introduce the dTGR model of retinal disease.

Decreased perfusion pressure modulates renin and ANG II type 1 receptor gene expression in the rat kidney

1993 ◽  
Vol 264 (4) ◽  
pp. R696-R702 ◽  
Author(s):  
A. Tufro-McReddie ◽  
R. L. Chevalier ◽  
A. D. Everett ◽  
R. A. Gomez
Keyword(s):  
Gene Expression ◽  
Aortic Coarctation ◽  
Perfusion Pressure ◽  
Receptor Gene ◽  
At1 Receptor ◽  
Northern Analysis ◽  
Renin Gene ◽  
Renin Mrna ◽  
Receptor Gene Expression

To determine whether decreased perfusion pressure affects the abundance and distribution of renin and its mRNA and the expression of the angiotensin II type 1 (AT1) receptor gene within the kidney, adult male Sprague-Dawley rats were subjected to aortic coarctation proximal to the renal arteries (Coarc, n = 8) and compared with sham-operated rats (Sham, n = 6). Renal renin distribution was determined by immunocytochemistry using a specific polyclonal antibody against rat renin. Renin mRNA was assessed by in situ hybridization to a 35S-labeled oligonucleotide complementary to rat renin mRNA. Kidney AT1 mRNA levels were determined by Northern analysis using a 1,133-base pair rat AT1 cDNA. Femoral arterial blood pressure, measured 24 h after surgery, was lower in Coarc than in Sham rats (75 +/- 5.4 vs. 122 +/- 2.3 mmHg, P < 0.05). Aortic coarctation increased the percent of juxtaglomerular apparatuses (%JGA) containing renin and its mRNA (85 +/- 2.5 and 66 +/- 2.8 vs. 49 +/- 5.3 and 36 +/- 1.7%, Coarc vs. Sham, P < 0.05) and the intensity of hybridization signals (497 +/- 89 vs. 71 +/- 12 grains/JGA, Coarc vs. Sham, P < 0.05). In addition, recruitment of renin gene expressing cells was observed along afferent arterioles in Coarc rats, whereas renin and its mRNA were limited to the JGAs in Sham rats. Renal AT1 receptor gene expression was threefold lower in Coarc than in Sham rats. We conclude that reduction of perfusion pressure after abdominal aortic coarctation acutely enhances renin gene expression and downregulates AT1 receptor gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute hypoxia stimulates renin secretion and renin gene expression in vivo but not in vitro

1997 ◽  
Vol 272 (4) ◽  
pp. R1105-R1111 ◽  
Author(s):  
T. Ritthaler ◽  
K. Schricker ◽  
F. Kees ◽  
B. Kramer ◽  
A. Kurtz
Keyword(s):  
Gene Expression ◽  
Acute Hypoxia ◽  
Primary Cultures ◽  
Renin Secretion ◽  
Plasma Norepinephrine ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Renin Gene ◽  
Renin Mrna

This study aimed at examining the influence of acute hypoxia on renin secretion and renin gene expression in the kidney. To this end, male Sprague-Dawley rats were exposed to severe hypoxic stress (8% O2) or to carbon monoxide (0.1% CO) for 6 h, and plasma renin activity (PRA) and renal renin mRNA levels were determined. PRA values increased from 3 to 13 and 10 ng angiotensin I x h(-1) x ml(-1), and renin mRNA levels increased by 120 and 100% during hypoxia and CO, respectively. Lowering the PO2 from 150 to 20 or 7 mmHg in the gas atmosphere of primary cultures of renal juxtaglomerular cells had no influence on renin secretion and renin gene expression after 6 and 20 h. Our findings thus suggest that both arterial and venous hypoxia can be powerful stimulators of renin secretion and renin gene expression in vivo. Because renal denervation did not prevent stimulation of the renin system by hypoxia, the effect could be indirectly mediated via the baroreceptor-macula densa mechanism. Another potential mediator of the effect could be circulating catecholamines, since we found that plasma norepinephrine increased from 0.7 to 1.5 and 2.4 ng/ml and plasma epinephrine increased from 0.3 to 1.4 and 2.7 ng/ml during hypoxia and CO inhalation, respectively.

Regulatory elements of human renin gene expression

1987 ◽  
Vol 19 ◽  
pp. S48-S48 ◽  
Author(s):  
D BURT ◽  
P KELLEY ◽  
J FLYNN ◽  
A NAFTILAN ◽  
V DZAU
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Human Renin ◽  
Renin Gene

Atrial natriuretic peptide and pressure natriuresis: interactions with the renin-angiotensin system

1989 ◽  
Vol 257 (5) ◽  
pp. R1169-R1174 ◽  
Author(s):  
H. L. Mizelle ◽  
J. E. Hall ◽  
D. A. Hildebrandt
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Renin Angiotensin System ◽  
Renal Perfusion ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Pressure Natriuresis ◽  
Atrial Natriuretic

The aim of this study was to quantitate the effects of increases in atrial natriuretic peptide (ANP), within the pathophysiological range, on the acute pressure natriuresis mechanism and the role of the renin-angiotensin system (RAS) in modulating these effects. Renal hemodynamics and electrolyte excretion were measured in anesthetized dogs while renal perfusion pressure (RPP) was controlled at three levels (120-122, 100, and 75 mmHg) with and without intrarenal infusion of ANP at 5 ng.kg-1.min-1. Sodium excretion was significantly higher during ANP infusion at RPP of 122 +/- 3 mmHg, averaging 55.8 +/- 13.7 during control and 113.3 +/- 23.3 mueq/min during ANP infusion. AT RPP of 101 +/- 1 mmHg, sodium excretion was 51.8 +/- 17.4 during control and 93.0 +/- 17.6 mueq/min during ANP infusion, but at RPP of 75 +/- 0 mmHg there was no difference in sodium excretion between control and ANP infusion. In a second set of dogs, angiotensin II (ANG II) formation was blocked with captopril (20 micrograms.kg-1.min-1), circulating (5 ng.kg-1.min-1), and the above protocol was repeated. When the RAS was fixed, the renal responses to ANP infusion were abolished, even at the higher pressure levels. These data indicate that ANP increases the slope of pressure natriuresis; at higher levels of RPP, ANP potentiates pressure natriuresis but not at lower pressures. In addition, part of this effect may be due to suppression of the RAS, because the ANP-induced shift in the pressure natriuresis relationship was abolished when circulating ANG II was maintained constant.

Aldosterone enhances renin gene expression in juxtaglomerular cells

2004 ◽  
Vol 286 (2) ◽  
pp. F349-F355 ◽  
Author(s):  
Jürgen Klar ◽  
Helga Vitzthum ◽  
Armin Kurtz
Keyword(s):  
Gene Expression ◽  
Primary Cultures ◽  
Cellular Level ◽  
Juxtaglomerular Cells ◽  
Mrna Levels ◽  
Renin Synthesis ◽  
Corticosteroid Hormones ◽  
Renin Gene ◽  
Renin Mrna ◽  
Mrna Half Life

The secretion and synthesis of renin as the key regulator of the renin-angiotensin-aldosterone system are directly controlled by ANG II in the sense of a negative feedback. Because we found that renal afferent arterioles including the juxtaglomerular portion express the mineralocorticoid receptor, we aimed to characterize a possible direct effect of aldosterone on renin synthesis and renin secretion at the level of renal juxtaglomerular cells. Aldosterone (100 nM) clearly enhanced renin mRNA levels in primary cultures of mouse juxtaglomerular cells prestimulated with isoproterenol (100 nM) but had no effect on the exocytosis of stored renin. Similarly, in the mouse juxtaglomerular cell line As4.1, aldosterone time and concentration dependently increased renin mRNA abundance and prorenin secretion up to 2.5-fold. Moreover, aldosterone potentiated cAMP-induced renin gene expression in As4.1 cells. The effect of aldosterone was inhibited by spironolactone and was mimicked by corticosteroid hormones but not by sex steroids. Aldosterone had no influence on basal renin promoter activity but increased the renin mRNA half-life about threefold. In summary, these data suggest that aldosterone exerts a direct positive effect on renin gene expression at the cellular level probably by stabilizing renin mRNA.

scholarly journals Renin gene expression in human kidney biopsies from patients with glomerulonephritis or graft rejection.

1995 ◽  
Vol 5 (7) ◽  
pp. 1469-1475
Author(s):  
J Wagner ◽  
S Volk ◽  
C C Haufe ◽  
A Ciechanowicz ◽  
M Paul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Graft Rejection ◽  
Enzyme Inhibitor ◽  
Quantitative Polymerase Chain Reaction ◽  
Internal Standard ◽  
Human Kidney ◽  
Endogenous Gene ◽  
Tumor Nephrectomy ◽  
Renin Gene ◽  
Renin Mrna

The expression of renin mRNA was determined by a quantitative polymerase chain reaction assay in 27 human kidney samples: (1) 15 biopsies of patients with glomerulonephritis with or without angiotensin-converting enzyme inhibitor (ACEI) treatment; (2) biopsies of six renal allografts with graft rejection; and (3) six biopsy samples from unaffected parts of tumor nephrectomy specimens as controls. After isolation of RNA, 0.5 to 1 microgram of total RNA was used for reverse transcription to generate cDNA. The human renin gene was subsequently amplified by the use of two primers spanning the second and third exons. Renin expression was quantified with a renin cDNA mutant as the internal standard. It exhibited the same primer binding sites as the endogenous gene but carried a 155-basepair deletion, thus yielding a shorter amplification product. The number of glomeruli was counted by microscopic transillumination immediately after biopsy (median, 9 per biopsy; range, 2 to 23). Renin mRNA was expressed as femtograms of renin mRNA per glomerulus. Renin gene expression was lower in glomerulonephritic patients without ACEI treatment compared with that in control tumor nephrectomy samples, i.e., 63 +/- 20 (N = 7) versus 250 +/- 50 fg (N = 6) of renin mRNA/glomerulus, (P < 0.02), although plasma renin concentration in the glomerulonephritic patients was in the normal range. Significantly higher renin mRNA expression was found in glomerulonephritic patients treated with ACEI, i.e., 210 +/- 50 (N = 8) compared with 63 +/- 20 (N = 7) fg of renin mRNA/glomerulus in patient not treated with ACEI (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Angiotensin-Converting Enzyme Inhibition and AT1 Receptor Blockade Modify the Pressure-Natriuresis Relationship by Additive Mechanisms in Rats with Human Renin and Angiotensinogen Genes

1999 ◽  
Vol 10 (8) ◽  
pp. 1669-1680
Author(s):  
EERO MERVAALA ◽  
BASTIAN DEHMEL ◽  
VOLKMAR GROSS ◽  
ANDREA LIPPOLDT ◽  
JÜRGEN BOHLENDER ◽  
...  
Keyword(s):  
Gene Expression ◽  
Angiotensin Converting Enzyme ◽  
Sodium Excretion ◽  
Ace Inhibition ◽  
No Synthase ◽  
Receptor Blockade ◽  
Converting Enzyme ◽  
Endothelial No Synthase ◽  
Human Renin ◽  
Pressure Natriuresis

Abstract. The intrarenal factors responsible for hypertension in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes are unclear. The pressure-natriuresis and -diuresis relationships in response to chronic angiotensin-converting enzyme (ACE) inhibition and AT1 receptor blockade were evaluated. Renal renin-angiotensin and nitric oxide (NO) system gene expression was also investigated. Six-week-old dTGR were treated for 3 wk with submaximal doses of cilazapril (10 mg/kg, orally) or losartan (10 mg/kg, orally) or with the drug combination. In untreated dTGR, pressure-natriuresis relationships were maximally shifted rightward by approximately 70 to 80 mmHg, and both renal blood flow (RBF) and GFR were markedly decreased. Submaximal cilazapril and losartan dosages both decreased systolic BP by 30 mmHg and shifted the pressure-natriuresis curves leftward by 25 to 30 mmHg. Cilazapril increased RBF and GFR to values observed in normotensive control animals but did not significantly affect fractional sodium excretion (FENa) or fractional water excretion (FEH2O) curves. In contrast, losartan had no significant effect on RBF or GFR but shifted the FENa and FEH2O curves leftward. The cilazapril and losartan combination completely normalized BP and shifted the pressure-natriuresis curves leftward more than did either drug alone. When cilazapril and losartan were administered at higher doses (30 mg/kg, orally), the two drugs equally shifted the pressure-natriuresis curves leftward, by 50 mmHg. Both drugs increased RBF and GFR; however, only losartan shifted FENa and FEH2O curves leftward. Human and rat renin and angiotensinogen genes were downregulated in dTGR and were increased by losartan and cilazapril treatments, whereas no changes in the expression of rat ACE and AT1A receptor genes were observed. Endothelial NO synthase expression was increased by cilazapril but not by losartan. Neither inducible NO synthase nor neural NO synthase gene expression was affected by drug treatments. Therefore, submaximal ACE inhibition enhanced sodium excretion mainly by increasing RBF and GFR, whereas submaximal AT1 receptor blockade decreased tubular sodium and water reabsorption. The combination of the two drugs produced an additive effect. The ACE inhibitor effects may involve increased endothelial NO synthase expression, perhaps related to the inhibition of bradykinin degradation.

Sign in / Sign up

Export Citation Format

Share Document