RNAi inhibition of mineralocorticoid receptors prevents the development of cold-induced hypertension

Sun, Zhongjie; Bello-Roufai, Mahajoub; Wang, Xiuqing

doi:10.1152/ajpheart.01319.2007

Cited by 31 publications

(35 citation statements)

References 41 publications

(54 reference statements)

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“…The VPR tail-cuff procedure can reliably monitor BP and is a common method for monitoring BP in our laboratory. 28,[56][57][58] Nevertheless, we realized the potential limitation of this method, which is not optimal, versus the telemetry system.…”

Section: Measurements Of Bpmentioning

confidence: 99%

Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation

Zhou

Chen

et al. 2015

Journal of the American Society of Nephrology

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Klotho (KL) is a newly discovered aging suppressor gene. In mice, the KL gene extends the lifespan when overexpressed and shortens the lifespan when disrupted. This study investigated if KL deficiency affects BP and salt sensitivity using KL mutant heterozygous (+/2) mice and wild-type (WT) mice (9 weeks of age, 16 mice per group). Notably, systolic BP in KL(+/2) mice began to increase at the age of 15 weeks, reached a peak level at the age of 17 weeks, and remained elevated thereafter, whereas systolic BP remained consistent in WT mice. High salt (HS) intake further increased BP in KL(+/2) mice but did not affect BP in WT mice. Blockade of CC chemokine receptor 2 (CCR2), involved in monocyte chemotaxis, by a specific CCR2 antagonist (INCB3284) abolished the HS-induced increase in BP in KL(+/2) mice. Furthermore, HS loading substantially increased the expression of monocyte chemotactic protein-1 and the infiltration of macrophages and T cells in kidneys in KL(+/2) mice, and treatment with INCB3284 abolished these effects. Treatment of KL(+/2) mice with INCB3284 also attenuated the increased renal expressions of serum glucocorticoid-regulated kinase 1, thiazide-sensitive NaCl cotransporter, and ATP synthase b along with the renal structural damage and functional impairment induced by HS loading. In conclusion, KL deficiency caused salt-sensitive hypertension and renal damage by CCR2-mediated inflammation. In 1997, a new aging suppressor gene was identified and named after the purported Greek Moira Klotho, 1 who spins the thread of life and controls the ultimate destiny of humans. Insertional mutation of mouse klotho gene resulted in extensive premature aging phenotypes and shortens lifespan. 1 However, overexpression of mouse klotho gene extended the lifespan by 20%-30% and rescued aging disorders. 2 Therefore, klotho is an antiaging gene.Aging is characterized by age-related deterioration in health. Hypertension is a common agingrelated disorder. The prevalence of hypertension increases with age. 3 On the basis of an epidemiologic study, 3 the prevalence of hypertension is more than doubled in the elderly than the young population. More than two thirds of individuals over age 65 years suffer from hypertension according to the Seventh Report of the Joint National Committee. 4 Salt intake is one of the main environmental factors contributing to the development of hypertension. An increase in salt sensitivity has been noted with advancing age in numerous studies. 5-9 Salt sensitivity is more common in the old than the young population. The relationship of age and salt sensitivity seems to be stronger in hypertensive than

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Section: Measurements Of Bpmentioning

confidence: 99%

Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation

Zhou

Chen

et al. 2015

Journal of the American Society of Nephrology

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“…51 Cold-induced hypertension was attenuated when a U6-driven shRNA against the mineralocorticoid receptor was systemically delivered by an AAV2 vector in rats 52 and mice. 53 A 50% reduction in expression of the receptor was documented in the kidney where hypertrophy was attenuated, but not in the heart or aorta. The precise cellular targets of the active vector remain to be characterized.…”

Section: Studies Of Complex Syndromes With Ncrnasmentioning

confidence: 99%

AAV vectors for RNA-based modulation of gene expression

Danos

2008

Gene Ther

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At the post-transcriptional level, gene expression is largely regulated through a network of molecular machines that regulate pre-mRNA maturation integrity, transport, translation and degradation. These processes are based on the formation of nucleoprotein complexes and require the recognition of sequence motifs on the RNA. By masking these targets with complementary RNA sequences forming Watson-Crick base pairing, it is possible to efficiently and specifically impact on the cell phenotype, or to compensate the deleterious effect of mutations. Here we review how the adeno-associated virus technology is being exploited for expressing non-coding RNAs in tissues such as the brain, muscle or liver, in functional genomic studies as well as for the development of novel therapeutic strategies.

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“…MR knockdown approaches have also been attempted using shRNA and siRNA treatments. Sun and coworkers injected MRshRNA expressing adeno-associated viral particles to the tail vein of adult mice and then assessed responses to cold-induced hypertension (Sun et al 2008). Mice were injected 48 h before cold exposure and blood pressure measured weekly for 4-5 weeks.…”

Section: Knockdown Of Mr Levels In Vivo By Antisense Mrna or Rnai Appmentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

Cole

Young

2017

Journal of Endocrinology

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The mineralocorticoid receptor (MR) mediates the actions of two important adrenal corticosteroid hormones, aldosterone and cortisol. The cell signalling roles of the MR in vivo have expanded enormously since the cloning of human MR gene 30 years ago and the first MR gene knockout in mice nearly 20 years ago. Complete ablation of the MR revealed important roles postnatally for regulation of kidney epithelial functions, with MR-null mice dying 1-2 weeks postnatally from renal salt wasting and hyperkalaemia, with elevated plasma renin and aldosterone. Generation of tissue-selective MR-deficient mice using Cre recombinase-LoxP gene targeting has made it possible to analyse mice lacking MR only in specific cell types. Targeting renal-specific MR has differentiated roles in specific compartments of the kidney. Ablating MR in neurons of the forebrain reinforced important roles of the MR in response to stress, behaviour and anxiety, but suggested a minimal role in maintaining basal HPA axis tone. Deletion of the MR in macrophages and other cell types of the cardiovascular system clearly defined important roles for the regulation of cardiovascular physiology and pathophysiology. Knockdown of MR mRNA in vivo using antisense/siRNA approaches, and similarly MR overexpression, has provided useful rodent models to study physiological roles of MR signalling in vivo. More recently, targeted mutation of specific domains of the MR such as the DBD has defined genomic vs non-genomic roles in vivo. New tissue-selective MR-null models are required to define roles of MR signalling in other regions of the brain, the eye, gastrointestinal tract, lung, skin, breast and gonadal organs.

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RNAi inhibition of mineralocorticoid receptors prevents the development of cold-induced hypertension

Cited by 31 publications

References 41 publications

Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation

Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation

AAV vectors for RNA-based modulation of gene expression

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

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