A Haplotype of Angiotensin Receptor Type 1 Associated with Human Hypertension Increases Blood Pressure in Transgenic Mice

Jain, Sudhir; Prater, Alicia; Pandey, Varunkumar; Rana, Anita; Puri, Nitin; Kumar, Ashok

doi:10.1074/jbc.m113.520023

Cited by 13 publications

(29 citation statements)

References 31 publications

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“…In this perspective, the observed haplotype block of four SNPs, represented primarily by Hap-I (TTAA) and Hap-II (AGCG) in the promoter of the hAT 1 R gene, provide a better model to understand the pathophysiology associated with it (Fig. 1) [17]. In our present study, we wanted to better understand the role of these haplotypes in the progression of diseases like stroke.…”

Section: Discussionmentioning

confidence: 99%

“…The TG mice utilized in this study were generated in our lab, as previously described by Jain et al [17]. Genotyping analysis of the tail snips, followed by sequencing, was performed to confirm the genetic lineage of these TG mice.…”

Section: Methodsmentioning

confidence: 99%

“…The increased inflammation and decreased vascular compliance in the cerebrovasculature due to over-expression of AT 1 R in SHRs were successfully reversed by AT 1 R blocker, candesartan [14–16]. Favoring these studies, we have recently published our results showing hypertension in TG mice overexpressing the human AT 1 R (hAT 1 R) gene [17]. Recent studies also show a reduction in agerelated development of hypertension in AT 1 R deficient mice [18].…”

Section: Introductionmentioning

confidence: 99%

“…1). We have shown that Hap-I of the hAT 1 R gene is associated with hypertension in the Caucasian population and has increased promoter activity on transient transfection of reporter constructs [17]. To better understand the molecular regulation and physiological roles of these haplotypes, we have generated transgenic (TG) mice containing Hap-I and II of the hAT 1 R gene in a 166 Kb bacterial artificial chromosome (BAC).…”

Section: Introductionmentioning

confidence: 99%

“…To better understand the molecular regulation and physiological roles of these haplotypes, we have generated transgenic (TG) mice containing Hap-I and II of the hAT 1 R gene in a 166 Kb bacterial artificial chromosome (BAC). We observed that Hap-I TG mice have increased hAT 1 R mRNA levels and increased expression of inflammatory markers, oxidative stress and BP, as compared to hAT 1 R TG mice containing Hap-II [17]. …”

Section: Introductionmentioning

confidence: 99%

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Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury

et al. 2015

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Hypertension is one of the co-morbid conditions for stroke and profoundly increases its incidence. Angiotensin II (AngII) is shown to be at the center stage in driving the renin angiotensin system via activation of angiotensin 1 receptor (AT1R). This makes the AT1R gene one of the candidates whose differential regulation leads to the predisposition to disorders associated with hypertension. A haplotype block of four SNPs is represented primarily by haplotype-I, or Hap-I (TTAA), and haplotype-II, or Hap-II (AGCG), in the promoter of human AT1R (hAT1R) gene. To better understand the physiological role of these haplotypes, transgenic (TG) mice containing haplotype-I and II of the hAT1R gene in a 166Kb BAC (bacterial artificial chromosome) were generated. Mice received injection of endothelin-1 (1mg/ml) directly in to the striatum and were evaluated for neurologic deficit scores and sacrificed for analysis of infarct volume and mRNA levels of various proteins. Mice containing Hap-I suffered from significantly higher neurological deficits (50%) and larger brain infarcts (60%) than Hap II. Similarly, the molecular analysis of oxidant and inflammatory markers in brains of mice showed a significant increase (p<0.05) in NOX-1 (2.3 fold), CRP (4.3 fold) and IL6 (1.9 fold) and a corresponding reduced expression of antioxidants SOD (60%) and HO-1 (55%) in Hap-I mice as compared to Hap-II mice. These results suggest that increased expression of hAT1R rendered Hap-I TG mice susceptible to stroke-related pathology, possibly due to increased level of brain inflammatory and oxidative markers and a suppressed antioxidant defense system.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury

et al. 2015

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Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

et al. 2017

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The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights into its current and emerging management. Considering that the intricate control of BP is governed by a myriad of anatomical, molecular biological, biochemical, and physiological systems, multiple genes are likely to influence an individual's BP and susceptibility to develop hypertension. The long-term regulation of BP rests on renal and non-renal mechanisms. One renal mechanism relates to sodium transport. The impaired renal sodium handling in primary hypertension and salt sensitivity may be caused by aberrant counter-regulatory natriuretic and anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin-aldosterone systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension, including that associated with obesity. We present updates on the complex interactions of these two systems with dietary salt intake in relation to obesity, insulin resistance, inflammation, and oxidative stress. We review how insults during pregnancy such as maternal and paternal malnutrition, glucocorticoid exposure, infection, placental insufficiency, and treatments during the neonatal period have long-lasting effects in the regulation of renal function and BP. Moreover, these effects have sex differences. There is a need for early diagnosis, frequent monitoring, and timely management due to increasing evidence of premature target organ damage. Large controlled studies are needed to evaluate the long-term consequences of the treatment of elevated BP during childhood, especially to establish the validity of the current definition and treatment of pediatric hypertension.

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Hormones Related to the Kidney and Cardiovascular System

Norman

Henry²

2015

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A Haplotype of Angiotensin Receptor Type 1 Associated with Human Hypertension Increases Blood Pressure in Transgenic Mice

Cited by 13 publications

References 31 publications

Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury

Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

Hormones Related to the Kidney and Cardiovascular System

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