Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II

Schunkert, Heribert; Ingelfinger, Julie R.; Jacob, Herbert; Jackson, Brian A.; Bouyounes, Boutros T.; Dzau, Victor J.

doi:10.1152/ajpendo.1992.263.5.e863

Cited by 106 publications

(110 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The immunoprecipitation of mouse renin indicated that the high plasma renin concentration was primarily transgene-derived, whereas in situ hybridization revealed suppression of kidney renin mRNA in the induced transgenic animals (presumably as a result of negative feedback (27)), confirming that the kidney was not the source of high circulating renin.…”

Section: Discussionmentioning

confidence: 97%

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

Kantachuvesiri¹,

Fleming²,

Peters³

et al. 2001

Journal of Biological Chemistry

142

297

View full text Add to dashboard Cite

A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.Essential hypertension has a complex multifactorial phenotype. Both genetic and environmental factors influence its development, and understanding the pathogenesis of complications such as vascular lesions and end-organ damage may lead to more specific treatment and targeted intervention.We have identified candidate loci in rats that may contribute to target organ damage and mortality in malignant hypertension (MH), 1 a condition characterized by an accelerated rise in blood pressure, endothelial injury, activation of the reninangiotensin system, and microangiopathy (1). Several animal models have been generated to investigate the pathophysiology of hypertensive vascular injury. Most animal models of MH to date require surgical or pharmacological intervention to precipitate onset or depend on the constitutive expression of endogenous genes or heterologous transgenes (2-5). In rats doubly transgenic for human renin and angiotensinogen genes, hypertension and fibrinoid vasculitis (5) accompanied by alteration in surface adhesion molecules, proinflammatory cytokines, fibrogenic mediators and leukocyte infiltration (6) have been reported. In most of these models, the onset of disease cannot be determined precisely.The initiation events of pathological processes can only be studied in an animal model in which hypertension is induced by tightly temporally regulated gene expression. If the onset and level of hypertension can be controlled, then the cellular and molecular events during initiation of the vascular and organ injury can be identified unequivocally. Reversibility of the gene expression provides an opportunity to study the molecular and cellular basis of repair. We therefore have generated inbred transgenic rats with inducible hypertension using the cytochrome P450 promoter, Cyp1a1, to drive expression of the mouse Ren-2 gene. The transgene is expressed primarily ...

show abstract

Section: Discussionmentioning

confidence: 97%

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

Kantachuvesiri¹,

Fleming²,

Peters³

et al. 2001

Journal of Biological Chemistry

142

297

View full text Add to dashboard Cite

show abstract

“…Ang II-infused rats have increases in renal angiotensinogen mRNA (11,26) and protein (12). Several in vitro studies have demonstrated Ang II-induced augmentation of angiotensinogen mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Intrarenal Angiotensinogen Contributes to Early Renal Injury in Spontaneously Hypertensive Rats

Kobori

Ozawa

Suzaki

et al. 2005

Journal of the American Society of Nephrology

147

168

View full text Add to dashboard Cite

This study was performed to determine whether augmented intrarenal angiotensinogen may contribute to the enhanced renal angiotensin II (Ang II) and associated tissue injury in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were maintained on a normal diet and killed at either 7 or 14 wk of age. Two groups of SHR received either an Ang II type 1 receptor blocker (ARB; olmesartan, 5 mg/d) or a triple therapy (hydralazine 7.5 mg/d, reserpine 0.15 mg/d, and hydrochlorothiazide 3 mg/d [HRH]) during weeks 7 through 14. Systolic BP and renal Ang II were significantly increased in SHR-14 (n ‫؍‬ 8) compared with WKY-7, WKY-14, and SHR-7 (n ‫؍‬ 8 each), and ARB treatment prevented these increases (n ‫؍‬ 8). However, whereas HRH treatment prevented the development of hypertension in SHR, this combination therapy failed to decrease renal Ang II (n ‫؍‬ 8). With the use of urine samples or fixed renal sections, renal injuries in rats were quantified in a semiautomated manner by the following six parameters: (1) urinary excretion rate of total protein, (2) glomerular sclerosis, (3) interstitial expansion, (4) and (5) numbers of monocytes/macrophages in interstitium or glomeruli, and (6) arterial proliferation. Angiotensinogen mRNA and protein levels in kidney cortex, measured by real-time reverse transcriptase-PCR and Western blot analysis, respectively, and all six parameters of renal damage were changed in parallel, and ARB treatment also prevented these increases. However, HRH treatment failed to prevent these increases. These results indicate that SHR have enhanced intrarenal angiotensinogen production that contributes to increased Ang II levels leading to the development of hypertension and renal injury in this strain. S pontaneously hypertensive rats (SHR) have been used as a model of hypertension (1). Mature SHR are reported to have low plasma renin activity (2), which has been interpreted as being indicative of an overall suppression of the renin-angiotensin system (RAS) (3). However, few studies of angiotensinogen have been carried out in these rats. Although generally considered to be characterized by a low activity of circulating RAS, recent studies indicate that treatment with angiotensin I (Ang I)-converting enzyme (ACE) inhibitors and/or Ang II type I (AT1) receptor blocker (ARB) reduces cardiac and/or renal dysfunction in SHR (4 -6). These findings suggest that the intrarenal RAS may be inappropriately activated and in turn contribute to the development of hypertension and hypertension-induced renal damages in this animal model.We recently reported that Dahl-salt sensitive rats on a highsalt diet have an inappropriate augmentation of intrarenal angiotensinogen, which may contribute to impaired sodium excretion and the development of hypertension in this strain (7,8). These results prompted us to perform further experiments to evaluate the intrarenal level of angiotensinogen in other animal models of hypertension. This study was performed to determine whether an augmented intrarenal angiot...

show abstract

“…It is speculated that an enhanced systemic generation of angiotensin II, which is a well known suppressor of renin gene expression [7,10,16,21], due to increased release of renin from the stenosed kidney, is causally involved in this process [17]. It should be of interest in this context that contralateral suppression of renin gene expression occurred also in furosemide-infused animals, in which PRA values did not further increase upon renal artery clipping.…”

Section: Discussionmentioning

confidence: 99%

Role of the macula densa in the control of renal renin gene expression in two-kidney/one-clip rats

et al. 1994

View full text Add to dashboard Cite

Abstract. This study was designed to examine whether macula densa function is involved in the changes of renal renin gene expression upon acute hypoperfusion of one kidney. To block macula densa function, rats with free access to salt and water were subcutaneously infused with furosemide (12 mg/day) for 6 days. Then, 4 days after the start of the infusion, the left renal arteries were clipped with 0.2-ram silver clips and renin mRNA levels in ipsilateral and contralateral kidneys, as well as plasma renin activities (PRA), were determined 48 h after clipping. In non-clipped animals furosemide increased PRA from 10 to 47 ng angiotensin I 9 h -1 9 ml 1 and raised renin mRNA levels in both kidneys 2.5-fold. In vehicle-infused animals, clipping of the left renal artery increased PRA to 37 ng angiotensin I. h -l. m1-1 and led to a 5-fold rise of renin mRNA levels in the ipsilateral kidneys and to a suppression to 20% of the control values in the contralateral kidneys. PRA values in clipped and furosemide-infused animals were 45 ng angiotensin I. h 1. ml-'. In these animals renin mRNA levels increased in the ipsilateral kidneys to similar absolute values as in vehicle-infused rats, whilst contralateral renin mRNA levels fell to about 25% of the respective controls. These findings indicate that the stimulations of renin gene expression by inhibition of macula densa salt transport and by renal artery clipping are not additive, suggesting that the macula densa mechanism may participate in the stimulation of renin gene expression upon hypoperfusion. The macula densa mechanism, however, appears to be not essentially involved in the suppression of renin gene expression in the contralaterals to stenosed kidneys.

show abstract

Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II

Cited by 106 publications

References 18 publications

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

Enhanced Intrarenal Angiotensinogen Contributes to Early Renal Injury in Spontaneously Hypertensive Rats

Role of the macula densa in the control of renal renin gene expression in two-kidney/one-clip rats

Contact Info

Product

Resources

About