Brain-Targeted (Pro)renin Receptor Knockdown Attenuates Angiotensin II–Dependent Hypertension

Li, Wencheng; Peng, Hua; Cao, Theresa; Sato, Ryosuke; McDaniels, S.J.; Kobori, Hiroyuki; Navar, L. Gabriel; Feng, Yi

doi:10.1161/hypertensionaha.111.190108

Cited by 92 publications

(123 citation statements)

References 28 publications

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“…A clue indicating a potential biological function of sPRR came from immunostaining of rat kidneys using antibodies against different domains of PRR. We examined the cellular localization of renal PRR in rats using two different antibodies: the antibody raised against the C-terminal domain of PRR (termed "anti-PRR-C antibody"; Abcam) and another antibody against the N-terminal domain in the sPRR sequence (termed "anti-PRR-N antibody") (24). After the cleavage, sPRR is recognized by anti-PPR-N but not by anti-PRR-C. Anti-PRR-C antibody labeled AQP2 − CD cells, e.g., the intercalated cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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135

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The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.soluble (pro)renin receptor | liver X receptor | aquaporin-2 | frizzled-8 | β-catenin F ull-length (Pro)renin receptor (PRR), a 350-amino acid transmembrane receptor for prorenin and renin, is subjected to protease-mediated cleavage to produce a 28-kDa protein of the N-terminal extracellular domain, the soluble (pro)renin receptor (sPRR), and the 8.9-kDa C-terminal intracellular domain called "M8.9" (1, 2). Before the cloning of full-length PRR in mesangial cells as an integral 39-kDa membrane protein (3), M8.9 was identified as a truncated protein associated with the vacuolar H + -ATPase (V-ATPase) from bovine chromatin granules (4). The cleavage occurs in Golgi apparatus through furin (5) or ADMA19 (6). An sPRR ELISA kit has been developed to detect sPRR in plasma and urine samples (7) . With this assay, increased serum sPRR levels have been demonstrated in patients with heart failure (8), kidney disease (9, 10), hypertension (11), and preeclampsia (2). Moreover, serum sPRR is positively associated with serum creatinine, blood urea nitrogen, and urine protein and is inversely associated with the estimated glomerular filtration rate in patients with chronic kidney disease caused by hypertension...

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Section: Resultsmentioning

confidence: 99%

“…A second anti-PRR antibody used in the present study raised against residues 218-235 in the N terminus of PRR (termed "anti-PRR-N antibody") was generated in Y.F. 's laboratory (24). Goat anti-AQP2 antibody was purchased from Santa Cruz.…”

Section: Methodsmentioning

confidence: 99%

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

135

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“…This may due to either an insufficient prorenin dose used for injection or low level of endogenous PRR expression in the PVN of normotensive rat. It has been reported that the expression of PRR in the central nervous system is relatively lower in normotensive animals compared with that in animals with hypertension (21,22,38). Therefore, it is possible that sympathoexcitation elicited by activation of PRR in the PVN might not be sufficient to elevate ABP in normotensive animals.…”

Section: Discussionmentioning

confidence: 97%

“…The importance of the brain PRR in cardiovascular control is further strengthened by the observation that increased PRR expression in brain cardiovascular control areas altered body fluid homeostasis (38) and genetic knockdown of the PRR induced long-term depressor effects in hypertensive animals (21,22,38). However, the detailed mechanism underlying the role of brain PRR on blood pressure regulation is not well understood.…”

Section: To Our Best Knowledge This Study Is the First To Investigatmentioning

confidence: 99%

“…With the use of a left flank incision, a left renal and splanchnic sympathetic nerve bundle was isolated from surrounding tissue (13,21,42), mounted on a stainless steel wire electrode (0.127-mm OD; A-M Systems), and covered with a silicon-based impression material (Light Body; Coltene) to insulate the recording from body fluids. The recorded signal was directed to an AC amplifier (P511; Grass Technologies) equipped with half-amplitude filters (band pass: 100-1,000 Hz) and a 60-Hz notch filter.…”

Section: Animalsmentioning

confidence: 99%

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Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Huber

Basu

Cecchettini

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats. Am J Physiol Heart Circ Physiol 309: H880 -H887, 2015. First published June 26, 2015 doi:10.1152/ajpheart.00095.2015.-Previous studies have indicated that hyperactivity of brain prorenin receptors (PRR) is implicated in neurogenic hypertension. However, the role of brain PRR in regulating arterial blood pressure (ABP) is not well understood. Here, we test the hypothesis that PRR activation in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA). In anaesthetized adult Sprague-Dawley (SD) rats, bilateral PVN microinjection of human prorenin (2 pmol/side) significantly increased splanchnic SNA (SSNA; 71 Ϯ 15%, n ϭ 7). Preinjection of either prorenin handle region peptide, the PRR binding blocker (PRRB), or tiron (2 nmol/side), the scavenger of reactive oxygen species (ROS), significantly attenuated the increase in SSNA (PRRB: 32 Ϯ 5% vs. control, n ϭ 6; tiron: 8 Ϯ 10% vs. control, n ϭ 5; P Ͻ 0.05) evoked by prorenin injection. We further investigated the effects of PRR activation on ROS production as well as downstream gene expression using cultured hypothalamus neurons from newborn SD rats. Incubation of brain neurons with human prorenin (100 nM) dramatically enhanced ROS production and induced a time-dependent increase in mRNA levels of inducible nitric oxide synthase (iNOS), NAPDH oxidase 2 subunit cybb, and FOS-like antigen 1 (fosl1), a marker for neuronal activation and a component of transcription factor activator protein-1 (AP-1). The maximum mRNA increase in these genes occurred 6 h following incubation (iNOS: 201-fold; cybb: 2 -fold; Ffosl1: 11-fold). The increases in iNOS and cybb mRNA were not attenuated by the AT 1 receptor antagonist losartan but abolished by the AP-1 blocker curcumin. Our results suggest that PVN PRR activation induces sympathoexcitation possibly through stimulation of an ANG II-independent, ROS-AP-1-iNOS signaling pathway. paraventricular nucleus; (pro)renin receptor; reactive oxygen species; sympathetic nerve activity NEW & NOTEWORTHY To our best knowledge, this study is the first to investigate PVN PRR-mediated ANG II-independent signaling transduction on the control of sympathetic outflow and blood pressure. Our results suggest that PVN PRR-induced sympathoexcitation is possibly mediated by ROS-AP-1-iNOS signal transduction pathways.ACCUMULATING EVIDENCE INDICATES that alteration of central (pro)renin receptor (PRR) is involved in the development of cardiovascular diseases including neurogenic hypertension (32,46). The importance of the brain PRR in cardiovascular control is further strengthened by the observation that increased PRR expression in brain cardiovascular control areas altered body fluid homeostasis (38) and genetic knockdown of the PRR induced long-term depressor effects in hypertensive animals (21,22,38). However, the detailed mechanism underlying the role of brain PRR on blood pressure regulati...

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Impact of the prorenin/renin receptor on the development of obesity and associated cardiometabolic risk factors

Tan

Shamansurova

Bisotto

et al. 2014

Obesity

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Objective: Obesity is a worldwide epidemic and current treatments have limited success thus, novel therapies are warranted. Our objective was to determine whether the prorenin/renin receptor [(P)RR] is implicated in obesity. Methods: Mice received a normal or high-fat/high-carbohydrate diet with the handle region peptide (HRP), a (P)RR blocker, or saline for 10 weeks. Post-menopausal non-diabetic obese women were enrolled in the Complication Associated with Obesity Study and were classified as insulin-resistant (IRO) or -sensitive (ISO) using a hyperinsulinemic-euglycemic clamp. Results: In mice, obesity increased the (P)RR by twofold in adipose tissue. Likewise, renin increased by at least twofold. The HRP reduced weight gain in obese mice by 20% associated to a 19% decrease in visceral fat. This was accompanied by a 48% decrease in leptin mRNA in fat and 33% decrease in circulating leptin. Inflammatory markers were also decreased by the HRP treatment. HRP normalized triglyceridemia and reduced insulinemia by 34% in obese mice. Interestingly, we observed a 33% increase in (P)RR mRNA in the fat of IRO women compared to ISO. Conclusions: This is the first report of a potential implication in obesity of the (P)RR which may be a novel therapeutic target.

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Brain-Targeted (Pro)renin Receptor Knockdown Attenuates Angiotensin II–Dependent Hypertension

Cited by 92 publications

References 28 publications

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Impact of the prorenin/renin receptor on the development of obesity and associated cardiometabolic risk factors

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