Liver X receptors   and   regulate renin expression in vivo

Morello, Fulvio

doi:10.1172/jci24594

Cited by 90 publications

(80 citation statements)

References 40 publications

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“…This possibility needs to be validated in future studies using LXRα-null mice. It has been shown that acute LXR activation induces a transient increase in renin transcription in the juxtaglomerular cells (32), but its chronic activation remarkably suppresses the expression of renin, AT1R, and angiotensin 1-converting enzyme 1 (ACE) in the heart and kidney following isoproterenol treatment (52). In agreement with the inhibitory effect of LXRs on local RAS, we found that TO901317 treatment remarkably suppressed urinary renin, an index of the intrarenal RAS (35,53).…”

Section: Induction Of Diabetes Insipidus and Suppression Of Renal Prrsupporting

confidence: 74%

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.

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: Induction Of Diabetes Insipidus and Suppression Of Renal Prrsupporting

confidence: 74%

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.

135

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“…This finding was confirmed recently using a mouse in vivo model. 6 Both LXR-␣ and LXR-␤ were shown to be regulators of renin transcription. Renal expression of LXR-␣ was found confined to JG cells (Figure 2).…”

Section: Liver X Receptorsmentioning

confidence: 99%

Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

et al. 2008

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T he renin-angiotensin-aldosterone system (RAAS) has been identified as the main system involved in blood pressure regulation, renal hemodynamics, and sodiumvolume homeostasis. Furthermore, the RAAS directly affects vascular and cardiac remodeling through proliferative and inflammatory signaling. Pharmacological targeting of the RAAS is a consolidated and evidence-based approach in the treatment of various aspects of cardiovascular disease. An exploding number of recent studies have provided novel insights into nuclear receptor biology in relation to cardiovascular (patho)physiology. In particular, members of the nuclear hormone receptor (NHR) superfamily have been identified as key molecules in various relevant cellular processes. As such, NHRs have been proposed as amenable targets for therapy, and their role in cardiovascular disease is currently explored.This review focuses on the potential effects of NHRs on the RAAS, summarizing the extensive body of evidence from experimental, animal, and clinical studies, suggesting that NHRs and the RAAS are closely intertwined. We discuss how these findings might translate into the clinical setting and discuss the (older) trials that evaluated NHR agonists in humans. We postulate that therapies targeting NHRs will cause ancillary effects (ie, modulating the RAAS) that need to be considered.

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“…Our mice exhibited varying sensitivities to STZ, which left the number of animals in some groups lower than anticipated. We did not perform an exhaustive survey of the RAS; however, it is notable that Lxrα/β −/− mice have previously been shown to have a blunted response to isoprenaline, suggesting that Lxrα/β −/− mice would be protected against (not susceptible to) hypertension [46]. DMHCA was very effective at decreasing circulating cholesterol and triacylglycerol levels with additional beneficial effects on liver lipid levels.…”

Section: Discussionmentioning

confidence: 97%

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

et al. 2013

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Aims/hypothesis Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes.Methods Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β +/+ (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β −/− mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N ,N -dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. Results Even in the absence of diabetes, Lxrα/β −/− mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β +/+ mice. When challenged with diabetes, Lxrα/β −/− mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. Conclusions/interpretation These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.

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Liver X receptors and regulate renin expression in vivo

Cited by 90 publications

References 40 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

Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

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