Transient renin–angiotensin system stimulation in an early stage of life causes sustained hypertension in rats

Heijnen, Bart F.J.; Peutz‐Kootstra, Carine J.; Mullins, John J.; Janssen, Ben J. A.; Struijker‐Boudier, Harry A.J.

doi:10.1097/hjh.0b013e32834cfcf4

Cited by 8 publications

(10 citation statements)

References 28 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prolonged activation of the RAS in Cyp1a1Ren2 rats causes hypertension, increased renal vascular resistance (as measured by flow probe), glomerulosclerosis and tubulointerstitial inflammation (Heijnen et al . , ). In addition, in Cyp1a1Ren2 rats, the kidney seems to be more at risk of development of injury than the heart, which showed only relatively mild maladaptation (i.e.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Exogenous and endogenous angiotensin‐II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

Emans

Janssen

Pinkham

et al. 2016

The Journal of Physiology

View full text Add to dashboard Cite

Key points Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary.We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats.This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation.Exogenous angiotensin‐II reduced renal cortical tissue PnormalO2 more than equi‐pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine.Activation of the endogenous renin–angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PnormalO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin‐II receptor type 1 antagonist.Angiotensin‐II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease. AbstractWe hypothesised that both exogenous and endogenous angiotensin‐II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PnormalO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PnormalO2 was dose‐dependently reduced by intravenous AngII. Reductions in PnormalO2 were significantly greater than those induced by equi‐pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min−1. Equi‐pressor infusion of phenylephrine did not significantly reduce RBF or renal oxygen delivery. Activation of the endogenous renin–angiotensin system in Cyp1a1Ren2 transgenic rats reduced cortical tissue PnormalO2. This could be reversed within minutes by pharmacological angiotensin‐II receptor type 1 (AT1R) blockade. Thus AngII is an important modulator of renal cortical oxygenation via AT1 receptors. AngII had a greater influence on cortical oxygenation than did phenylephrine. This phenomenon appears to be attributable to the profound impact of AngII on renal oxygen delivery. We conclude that the ability of AngII to promote renal cortical hypoxia may contribute to its influence on initiation and progression of chronic kidney disease.

show abstract

Section: Discussionmentioning

confidence: 99%

“…This model is known to develop inducible AngII‐dependent hypertension and ultimately CKD when renin activation is prolonged for 4 weeks or more (Heijnen et al . , , ). We determined whether renal cortical hypoxia is an early event in this process and whether it can be reversed by AT 1 R blockade (Heijnen et al .…”

Section: Introductionmentioning

confidence: 99%

Exogenous and endogenous angiotensin‐II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

Emans

Janssen

Pinkham

et al. 2016

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that the long-lasting BP change in young IHR is due to irreversible renal damage following mRen2 activation. 5,6 Perspectives In IHR, mRen2 gene-related malignant hypertension induces fully reversible myocardial concentric hypertrophy with characteristics of diastolic heart failure, whereas in the related TGR strain systolic heart failure develops. Despite marked LV concentric hypertrophy and reduced stroke volume, the absence of interstitial fibrosis and inflammation may make the IHR model not a true diastolic failure model but rather a model with benign reversible hypertrophy.…”

Section: Several Factors May Have Contributed To the Characteristic Cmentioning

confidence: 99%

“…Using this approach it was shown that transient RAS-stimulation induced sustained hypertension in young, but not adult IHR. 5,6 Most studies in IHR have been focusing on the kidney 5,7,8 and thus information on the cardiac remodeling processes in this model is limited.…”

Section: Introductionmentioning

confidence: 99%

Cardiac remodeling during and after renin–angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

Heijnen

Pelkmans

Danser

et al. 2013

J Renin Angiotensin Aldosterone Syst

View full text Add to dashboard Cite

This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically and the hearts were excised for molecular and immunohistochemical analyses. Echocardiographic studies revealed that four weeks of RAS-stimulation incited a cardiac remodeling process characterized by increased left ventricular (LV) wall thickness, decreased LV volumes, and shortening of the left ventricle. Hypertrophic genes were highly upregulated, whereas in substantial activation a fibrotic response was absent. Four weeks after withdrawal of I3C, (pro)renin levels were normalized in all IHR. While in adult IHR BP returned to normal, hypertension was sustained in young IHR. Despite the latter, myocardial hypertrophy was fully regressed in both young and adult IHR. We conclude that (pro)renin-induced severe hypertension in IHR causes an age-independent fully reversible myocardial concentric hypertrophic remodeling, despite a continued elevated BP in young IHR.

show abstract

“…Similarly, most studies using this model focus on acute hypertension, with few data in terms of chronic hypertension. 13,15,30,31 We therefore aimed to outline the breeding performance and productivity of transgenic Cyp1a1-Ren2 rats, demonstrate the inducible and reversible dose-dependent hypertension in this model, and describe the effect of chronic dosing with I3C on inducible hypertension.…”

mentioning

confidence: 99%

Breeding Characteristics and Dose-dependent Blood Pressure Responses of Transgenic Cyp1a1–Ren2 Rats

et al. 2018

View full text Add to dashboard Cite

Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent model (transgenic male Cyp1a1-Ren2 rats) provides reversible induction of hypertension through the addition of indole-3-carbinol (I3C) to the diet, without the need for surgical intervention, thus giving researchers control over both the onset of hypertension and its magnitude (I3C dose-dependency). We here report the breeding performance and productivity of Cyp1a1-Ren2 rats. Despite being transgenic, these animals proved to be efficient breeders. In addition to confirming inducible and reversible dose-dependent hypertension (by using I3C doses of 0.125%, 0.167%, and 0.25% [w/w] in the diet for 14 d, followed by normal chow for 4 d), we demonstrated that hypertension can be sustained chronically (14 wk) by continuous dosing with I3C (0.167% [w/w]) in the diet. In chronically dosed male rats, systolic blood pressure continued to rise, from 173 ± 11 mm Hg after 1 mo to 196 ± 19 mm Hg after 3 mo, with no adverse phenotypic features observed. In conclusion, Cyp1a1-Ren2 rats are a useful animal model to investigate hypertension-induced end-organ damage and potential new therapeutic targets to manage hypertension.

show abstract

Transient renin–angiotensin system stimulation in an early stage of life causes sustained hypertension in rats

Abstract: Transient RAS stimulation causes sustained elevation in BP in young, but not in adult Cyp1a1-Ren2 transgenic rats and is associated with irreversible changes in renal structure and function and a moderate renal inflammatory response.

Cited by 8 publications

References 28 publications

Exogenous and endogenous angiotensin‐II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

Exogenous and endogenous angiotensin‐II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

Cardiac remodeling during and after renin–angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

Breeding Characteristics and Dose-dependent Blood Pressure Responses of Transgenic Cyp1a1–Ren2 Rats

Contact Info

Product

Resources

About