Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, which can progress to nonalcoholic steatohepatitis (NASH). Histone deacetylase Sirtuin 6 (SIRT6) regulates NAFLD by regulating metabolism-related gene expression, but an extrachromosomal role for SIRT6 in NAFLD development remains elusive. We investigated whether SIRT6 functions on NAFLD in the cytoplasm. We found that SIRT6 binds saturated fatty acids, especially palmitic acid. This binding leads to its nuclear export, where it deacetylates long-chain acyl-CoA synthase 5 (ACSL5), thereby facilitating fatty acid oxidation. High-fat diet-induced NAFLD is suppressed by ACSL5 hepatic overexpression but is exacerbated by its depletion. As confirmation, overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in Sirt6 liver-specific knockout mice. Moreover, NASH-hepatic tissues from both patients and diet-fed mice exhibited significantly reduced cytoplasmic SIRT6 levels and increased ACSL5 acetylation. The SIRT6/ACSL5 signaling pathway has a critical role in NAFLD progression and might constitute an avenue for therapeutic intervention.

Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis.

BACKGROUND: Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H+-ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD+ (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase. METHODS: Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [3H]chloroquine (endosomal pH), and [14C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V1G1/V0d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload. RESULTS: NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions. CONCLUSION: NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.

Adipokine chemerin overexpression in trophoblasts leads to dyslipidemia in pregnant mice: implications for preeclampsia.

BACKGROUND: The adipokine chemerin regulates adipogenesis and the metabolic function of both adipocytes and liver. Chemerin is elevated in preeclamptic women, and overexpression of chemerin in placental trophoblasts induces preeclampsia-like symptoms in mice. Preeclampsia is known to be accompanied by dyslipidemia, albeit via unknown mechanisms. Here, we hypothesized that chemerin might be a contributor to dyslipidemia. METHODS: Serum lipid fractions as well as lipid-related genes and proteins were determined in pregnant mice with chemerin overexpression in placental trophoblasts and chemerin-overexpressing human trophoblasts. In addition, a phospholipidomics analysis was performed in chemerin-overexpressing trophoblasts. RESULTS: Overexpression of chemerin in trophoblasts increased the circulating and placental levels of cholesterol rather than triglycerides. It also increased the serum levels of lysophosphatidic acid, high-density lipoprotein cholesterol (HDL-C), and and low-density lipoprotein cholesterol (LDL-C), and induced placental lipid accumulation. Mechanistically, chemerin upregulated the levels of peroxisome proliferator-activated receptor g, fatty acid-binding protein 4, adiponectin, sterol regulatory element-binding protein 1 and 2, and the ratio of phosphorylated extracellular signal-regulated protein kinase (ERK)1/2 / total ERK1/2 in the placenta of mice and human trophoblasts. Furthermore, chemerin overexpression in human trophoblasts increased the production of lysophospholipids and phospholipids, particularly lysophosphatidylethanolamine. CONCLUSIONS: Overexpression of placental chemerin production disrupts trophoblast lipid metabolism, thereby potentially contributing to dyslipidemia in preeclampsia.

Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms.

Maternal circulating levels of the adipokine chemerin are elevated in preeclampsia, but its origin and contribution to preeclampsia remain unknown. We therefore studied (1) placental chemerin expression and release in human pregnancy, and (2) the consequences of chemerin overexpression via lentivirus-mediated trophoblast-specific gene manipulation in both mice and immortalized human trophoblasts. Placental chemerin expression and release were increased in women with preeclampsia, and their circulating chemerin levels correlated positively with the soluble Fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, a well-known biomarker of preeclampsia severity. Placental trophoblast chemerin overexpression in mice induced a preeclampsia-like syndrome, involving hypertension, proteinuria, and endotheliosis, combined with diminished trophoblast invasion, a disorganized labyrinth layer, and up-regulation of sFlt-1 and the inflammation markers nuclear factor-κB (NFκB), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß. It also led to embryo resorption, while maternal serum chemerin levels correlated negatively with fetal weight in mice. Chemerin overexpression in human trophoblasts up-regulated sFlt-1, reduced vascular endothelial factor-A, and inhibited migration and invasion, as well as tube formation during co-culture with human umbilical vein endothelial cells (HUVECs). The chemokine-like receptor 1 (CMKLR1) antagonist α-NETA prevented the latter phenomenon, although it did not reverse the chemerin-induced down-regulation of the phosphoinositide 3-kinase/Akt pathway. In conclusion, up-regulation of placental chemerin synthesis disturbs normal placental development via its CMKLR1 receptor, thereby contributing to fetal growth restriction/resorption and the development of preeclampsia. Chemerin might be a novel biomarker of preeclampsia, and inhibition of the chemerin/CMKLR1 pathway is a promising novel therapeutic strategy to treat preeclampsia.

Targeted chemical pressure yields tuneable millimetre-wave dielectric.

Epitaxial strain can unlock enhanced properties in oxide materials, but restricts substrate choice and maximum film thickness, above which lattice relaxation and property degradation occur. Here we employ a chemical alternative to epitaxial strain by providing targeted chemical pressure, distinct from random doping, to induce a ferroelectric instability with the strategic introduction of barium into today's best millimetre-wave tuneable dielectric, the epitaxially strained 50-nm-thick n = 6 (SrTiO3)nSrO Ruddlesden-Popper dielectric grown on (110) DyScO3. The defect mitigating nature of (SrTiO3)nSrO results in unprecedented low loss at frequencies up to 125 GHz. No barium-containing Ruddlesden-Popper titanates are known, but the resulting atomically engineered superlattice material, (SrTiO3)n-m(BaTiO3)mSrO, enables low-loss, tuneable dielectric properties to be achieved with lower epitaxial strain and a 200% improvement in the figure of merit at commercially relevant millimetre-wave frequencies. As tuneable dielectrics are key constituents of emerging millimetre-wave high-frequency devices in telecommunications, our findings could lead to higher performance adaptive and reconfigurable electronics at these frequencies.

Megalin, Proton Pump Inhibitors and the Renin-Angiotensin System in Healthy and Pre-Eclamptic Placentas.

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin-angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, including megalin, a novel endocytic receptor for prorenin and renin, in placental tissue obtained from healthy pregnant women and women with early-onset pre-eclampsia. Renin, ACE, ACE2, and the angiotensin receptors were expressed at identical levels in healthy and pre-eclamptic placentas, while both the (pro)renin receptor and megalin were increased in the latter. Placental prorenin levels were upregulated in pre-eclamptic pregnancies. Angiotensinogen protein, but not mRNA, was detectable in placental tissue, implying that it originates from maternal blood. Ex vivo placental perfusion revealed a complete washout of angiotensinogen, while prorenin release remained constant. The PPI esomeprazole dose-dependently reduced megalin/(pro)renin receptor-mediated renin uptake in Brown Norway yolk sac epithelial cells and decreased sFlt-1 secretion from placental villous explants. Megalin inhibition blocked angiotensinogen uptake in epithelial cells. In conclusion, our data suggest that placental RAS activity depends on angiotensinogen taken up from the maternal systemic circulation. PPIs might interfere with placental (pro)renin-AGT uptake/transport, thereby reducing angiotensin formation as well as angiotensin-induced sFlt-1 synthesis.

(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis.

RATIONALE: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin-angiotensin system. OBJECTIVES: To investigate the physiological role of (P)RR in lipid metabolism in vivo. METHODS AND RESULTS: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal- or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis. CONCLUSIONS: Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.

Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?

PURPOSE OF REVIEW: Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen. Indeed, without megalin urinary renin and angiotensinogen levels massively increase, and even prorenin becomes detectable in urine. RECENT FINDINGS: Intriguingly, megalin might also contribute to renal angiotensin production, as evidenced from studies in megalin knockout mice. This review discusses these topics critically, concluding that urinary renin-angiotensin system components reflect diminished reabsorption rather than release from renal tissue sites and that alterations in renal renin levels or megalin-dependent signaling need to be ruled out before concluding that angiotensin production at renal tissue sites is truly megalin dependent. Future studies should evaluate megalin-mediated renin/angiotensinogen transcytosis (allowing interstitial angiotensin generation), and determine whether megalin prefers prorenin over renin, thus explaining why urine normally contains no prorenin.

Revisiting the Brain Renin-Angiotensin System-Focus on Novel Therapies.

PURPOSE OF REVIEW: Although an independent brain renin-angiotensin system is often assumed to exist, evidence for this concept is weak. Most importantly, renin is lacking in the brain, and both brain angiotensinogen and angiotensin (Ang) II levels are exceptionally low. In fact, brain Ang II levels may well represent uptake of circulating Ang II via Ang II type 1 (AT1) receptors. RECENT FINDINGS: Nevertheless, novel drugs are now aimed at the brain RAS, i.e., aminopeptidase A inhibitors should block Ang III formation from Ang II, and hence diminish AT1 receptor stimulation by Ang III, while AT2 and Mas receptor agonists are reported to induce neuroprotection after stroke. The endogenous agonists of these receptors and their origin remain unknown. This review addresses the questions whether independent angiotensin generation truly occurs in the brain, what its relationship with the kidney is, and how centrally acting RAS blockers/agonists might work.

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism.

RATIONALE: The (pro)renin receptor ([P]RR) interacts with (pro)renin at concentrations that are >1000× higher than observed under (patho)physiological conditions. Recent studies have identified renin-angiotensin system-independent functions for (P)RR related to its association with the vacuolar H(+)-ATPase. OBJECTIVE: To uncover renin-angiotensin system-independent functions of the (P)RR. METHODS AND RESULTS: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins. This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density lipoprotein (LDL) receptor protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of epidermal growth factor or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDL receptor and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDL receptor induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1. CONCLUSIONS: Our study identifies a renin-angiotensin system-independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDL receptor.

Phenolic Compounds from Belamcanda chinensis Seeds.

Two new sucrose derivatives, namely, belamcanosides A (1) and B (2), together with five other known compounds (3-7), were isolated from the seeds of Belamcanda chinensis (L.) DC. Their structures were identified based on spectroscopic data. Especially, the absolute configurations of fructose and glucose residues in 1 and 2 were assigned by acid hydrolysis, followed by derivatization and gas chromatography (GC) analysis. Among the known compounds, (-)-hopeaphenol (3), (+)-syringaresinol (4), and quercetin (5), were isolated from B. chinensis for the first time. In addition, biological evaluation of 1 and 2 against cholesterol synthesis and metabolism at the gene level was carried out. The results showed that compounds 1 and 2 could regulate the expression of cholesterol synthesis and metabolism-associated genes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), squalene epoxidase (SQLE), low density lipoprotein receptor (LDLR), and sortilin (SORT1) genes in HepG2 cells.

Three New Polyynes from Codonopsis pilosula and Their Activities on Lipid Metabolism.

Three new polyynes, named choushenpilosulynes A-C (1-3), were isolated from an 85% aqueous EtOH extract of the roots of Codonopsis pilosula cultivated in Xundian County of Yunnan province, China. Their structures, including the absolute configuration of the glucose residue in 1 and 2, were determined by spectroscopic analysis and gas chromatography (GC). In addition, biological evaluation shows that all the compounds can inhibit the expression of the squalene monooxygenase (SQLE) gene in HepG2 cells, suggesting that these compounds may be involved in lipid metabolism.

(Pro)renin receptor as a therapeutic target for the treatment of cardiovascular diseases?

The discovery of the (pro)renin receptor [(P)RR] 15years ago stimulated ideas on prorenin being more than renin's inactive precursor. Indeed, binding of prorenin to the (P)RR induces a conformational change in the prorenin molecule, allowing it to display angiotensin-generating activity, and additionally results in intracellular signaling in an angiotensin-independent manner. However, the prorenin levels required to observe these angiotensin-dependent and -independent effects of the (P)RR are many orders above its in vivo concentrations, both under normal and pathological conditions. Given this requirement, the idea that the (P)RR has a function within the renin-angiotensin system (RAS) is now being abandoned. Instead, research is now focused on the (P)RR as an accessory protein of vacuolar H+-ATPase (V-ATPase), potentially determining its integrity. Acting as an adaptor between Frizzled co-receptor LRP6 and V-ATPase, the (P)RR appears to be indispensable for Wnt/ß-catenin signaling, thus explaining why (P)RR deletion (unlike renin deletion) is lethal even when restricted to specific cells, such as cardiomyocytes, podocytes and smooth muscle cells. Furthermore, recent studies suggest that the (P)RR may play important roles in lipoprotein metabolism and overall energy metabolism. In this review, we summarize the controversial RAS-related effects of the (P)RR, and critically review the novel non-RAS-related functions of the (P)RR, ending with a discussion on the potential of targeting the (P)RR to treat cardiovascular diseases.

Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit.

Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H+-ATPase subunit Vod1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy. Methods and Results: Atp6v0d1AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The Atp6v0d1AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1AKO mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1AKO hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1AKO mice. Conclusion: Atp6v0d1AKO mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy.

Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.

The (pro)renin receptor. A decade of research: what have we learned?

The discovery of a (pro)renin receptor ((P)RR) in 2002 provided a long-sought explanation for tissue renin-angiotensin system (RAS) activity and a function for circulating prorenin, the inactive precursor of renin, in end-organ damage. Binding of renin and prorenin (referred to as (pro)renin) to the (P)RR increases angiotensin I formation and induces intracellular signalling, resulting in the production of profibrotic factors. However, the (pro)renin concentrations required for intracellular signalling in vitro are several orders of magnitude above (patho)physiological plasma levels. Moreover, the phenotype of prorenin-overexpressing animals could be completely attributed to angiotensin generation, possibly even without the need for a receptor. The efficacy of the only available putative (pro)renin receptor blocker handle region peptide remains doubtful, leading to inconclusive results. The fact that, in contrast to other RAS components, (P)RR knock-outs, even tissue-specific, are lethal, points to an important, (pro)renin-independent, function of the (P)RR. Indeed, recent research has highlighted ancillary functions of the (P)RR as an essential accessory protein of the vacuolar-type H(+)-ATPase (V-ATPase), and in this role, it acts as an intermediate in Wnt signalling independent of (pro)renin. In conclusion, (pro)renin-dependent signalling is unlikely in non-(pro)renin synthesizing organs, and the (P)RR role in V-ATPase integrity and Wnt signalling may explain some, if not all of the phenotypes previously associated with (pro)renin-(P)RR interaction.

(Pro)renin receptor is required for prorenin-dependent and -independent regulation of vacuolar H⁺-ATPase activity in MDCK.C11 collecting duct cells.

Prorenin binding to the prorenin receptor [(P)RR] results in nonproteolytic activation of prorenin but also directly (i.e., independent of angiotensin generation) activates signal transduction cascades that can lead to the upregulation of profibrotic factors. The (P)RR is an accessory protein of vacuolar-type H⁺-ATPase (V-ATPase) and is required for V-ATPase integrity. In addition, in collecting duct cells, prorenin-induced activation of Erk depends on V-ATPase activity. However, whether prorenin binding to the (P)RR directly regulates V-ATPase activity is as yet unknown. Here, we studied the effect of prorenin on plasma membrane V-ATPase activity in Madin-Darby canine kidney clone 11 (MDCK.C11) cells, which resemble intercalated cells of the collecting duct. Prorenin increased V-ATPase activity at low nanomolar concentrations, and the V-ATPase inhibitor bafilomycin A1, but not the angiotensin II type 1 and 2 receptor blockers irbesartan and PD-123319, prevented this. Increased, but not basal, V-ATPase activity was abolished by small interfering RNA depletion of the (P)RR. Unexpectedly, the putative peptidic (P)RR blocker handle region peptide also increased V-ATPase activity in a (P)RR-dependent manner. Finally, [Arg8]-vasopressin-stimulated V-ATPase activity and cAMP production were also abolished by (P)RR depletion. Our results show that in MDCK.C11 cells, the (P)RR is required for prorenin-dependent and -independent regulation of V-ATPase activity.

The intrarenal renin-angiotensin system: does it exist? Implications from a recent study in renal angiotensin-converting enzyme knockout mice.

A large body of evidence supports the presence of local production of angiotensins in the kidney. It is widely believed that renin-angiotensin system (RAS) blockers, through interference with such production and/or the local effects of angiotensin (Ang) II, exert protective renal effects. Yet, whether such production affects blood pressure independently from the circulating RAS is still a matter of debate. To investigate this, a recent study by Gonzalez-Villalobos et al. (J Clin Invest 2013; 123: 2011-2023) has studied the consequences of infusing Ang II or the nitric oxide synthase inhibitor l-NAME in mice lacking renal angiotensin-converting enzyme (ACE). They observed blunted blood pressure and renal responses in the renal ACE knockout mice versus wild-type controls. This review discusses to what degree these findings can be considered as unequivocal evidence for ACE-mediated Ang II formation in the kidney as an independent determinant of hypertension.

The Role of Chemerin in Metabolic and Cardiovascular Disease: A Literature Review of Its Physiology and Pathology from a Nutritional Perspective.

Chemerin is a novel adipokine that plays a major role in adipogenesis and lipid metabolism. It also induces inflammation and affects insulin signaling, steroidogenesis and thermogenesis. Consequently, it likely contributes to a variety of metabolic and cardiovascular diseases, including atherosclerosis, diabetes, hypertension and pre-eclampsia. This review describes its origin and receptors, as well as its role in various diseases, and subsequently summarizes how nutrition affects its levels. It concludes that vitamin A, fat, glucose and alcohol generally upregulate chemerin, while omega-3, salt and vitamin D suppress it. Dietary measures rather than drugs acting as chemerin receptor antagonists might become a novel tool to suppress chemerin effects, thereby potentially improving the aforementioned diseases. However, more detailed studies are required to fully understand chemerin regulation.

Relationship between Employee Mental Health and Job Performance: Mediation Role of Innovative Behavior and Work Engagement.

The relationship between employee mental health and job performance has been one of the key concerns in workplace. However, extant studies suffer from incomplete results due to their focus on developed economies' contexts and the unclear path of employee mental health's impact on performance. In this paper, we investigate the mechanism of employee mental health influencing job performance. We use the data of Chinese firms to test these hypotheses. Drawing on a sample of 239 firms from China, we find that employee mental health positively impacts job performance, and such relationship is mediated by innovative behavior and work engagement. The findings not only enrich the discipline's knowledge on mental health in an emerging economy setting but also extend the implications of mental health, innovative behavior, and work engagement to job performance.