Modulation Of Renin Secretion By Renal Cortical Interstitial Calcium

Renin is secreted from the juxtaglomerular (JG) cells of the afferent arteriole of the kidney, and is the rate-limiting enzyme of the renin-angiotensin system. Renin is quantified in vivo as plasma renin activity (PRA). Acutely elevating plasma calcium decreases PRA, but the mechanisms by which this occurs is unknown. The overall goal of our study was to determine how elevated plasma calcium decreases PRA. The calcium-sensing receptor (CaSR) is a ubiquitously expressed receptor that translates changes in plasma calcium into changes in intracellular signaling. JG cells are basolaterally bordered by the renal cortical interstitium, and parathyroid hormone (PTH) positively regulates the concentration of calcium in the renal interstitium. Thus, we hypothesized that hypercalcemia inhibits PRA via PTH-mediated increases in renal cortical interstitial Ca that act on the CaSR triggering Ca-mediated inhibition of renin secretion. We demonstrated that the CaSR is expressed in JG cells in vivo. Additionally, we demonstrated that acutely stimulating the CaSR with pharmacological agonists decrease basal and stimulated PRA in anesthetized rats in parathyroid-intact and parathyroidectomized (PTX) rats. We demonstrated that acute hypercalcemia decreased PRA, and that this inhibition of PRA is blocked by pharmacological CaSR antagonists and by PTX. Acute supplementation of PTH did not affect the inhibition of PRA by high calcium. Acute hypercalcemia increased renal cortical interstitial calcium, and this effect was blocked by PTX. This was likely due to decreased expression of the PTH-sensitive distal tubule calcium transporter TRPV5. Lastly, we demonstrated that increasing renal sodium chloride delivery failed to increase renal cortical interstitial calcium, and that inhibiting thick ascending limb sodium chloride reabsorption with Furosemide increased PRA without effecting major changes in renal cortical interstitial calcium. Our data support the notion that hypercalcemia inhibits PRA via PTH-mediated increases in renal cortical interstitial Ca that act on the CaSR

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Anandamide inhibits transport-related oxygen consumption in the loop of Henle by activating CB1 receptors

The energy required for active Na chloride reabsorption in the thick ascending limb (TAL) depends on oxygen consumption and oxidative phosphorylation (OXP). In other cells, Na transport is inhibited by the endogenous cannabinoid anandamide through the activation of the cannabinoid receptors (CB) type 1 and 2. However, it is unclear whether anandamide alters TAL transport and the mechanisms that could be involved. We hypothesized that anandamide inhibits TAL transport via activation of CB1 receptors and NO. For this, we measured oxygen consumption (QO2) in TAL suspensions to monitor the anandamide effects on transport and OXP. Anandamide reduced QO2 in a concentration-dependent manner. During Na-K-2Cl cotransport and Na/H exchange inhibition, anandamide did not inhibit TAL QO2. To test the role of the cannabinoid receptors, we used specific agonists and antagonists of CB1 and CB2 receptors. The CB1-selective agonist WIN55212–2 reduced QO2 in a concentration-dependent manner. Also, the CB1 receptor antagonist rimonabant blocked the effect of anandamide on QO2. In contrast, the CB2-selective agonist JHW-133 had no effect on QO2, while the CB2 receptor antagonist AM-630 failed to block the anandamide effects on QO2. To confirm these results, we measured CB1 and CB2 receptor expression and only CB1 expression was detected. Because CB1 receptors are strong nitric oxide synthase (NOS) stimulators and NO inhibits transport in TALs, we evaluated the role of NO. Anandamide stimulated NO production and the NOS inhibitor NG-nitro-l-arginine methyl ester blocked the anandamide effects on QO2. We conclude that anandamide inhibits TAL Na transport-related QO2 via activation of CB1 receptor and NOS.Fil: Silva, Guillermo Benjamin. Universidad Católica de Córdoba; Argentina. Fundación Robert Cade; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Atchison, Douglas K.. Wayne State University; Estados Unidos. Henry Ford Hospital; Estados UnidosFil: Juncos, Luis Isaias. Fundación Robert Cade; ArgentinaFil: Garcia, Nestor Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentin

Phospholipase Cε insufficiency causes ascending aortic aneurysm and dissection

Phospholipase Cε (PLCε) is a phospholipase C isoform with a wide range of physiologic functions. It has been implicated in aortic valve disorders but its role in frequently associated aortic disease remains unclear. To determine the role of PLCε in thoracic aortic aneurysm and dissection (TAAD) we used PLCε deficient mice which develop aortic valve insufficiency and also exhibit aortic dilation of the ascending thoracic aorta and arch without histopathological evidence of injury. Fourteen days of infusion of Plce1(+/+) and Plce1(-/-) mice with angiotensin II (Ang II), which induces aortic dilation and dissection, lead to sudden death secondary to ascending aortic dissection in 43% of Plce1(-/-)versus 5% of Plce1(+/+) mice (p\u3c0.05). Medial degeneration and TAAD were detected in 80% of Plce1(-/-) compared to 10% of Plce1(+/+) mice (p\u3c0.05) after four days of Ang II. Treatment with Ang II markedly increased PLCε expression within the ascending aortic adventitia. RNA sequencing of ascending aorta tissue prior to aortic rupture demonstrated marked increased expression of pro-inflammatory and fibrotic signaling pathways, as well as upstream regulators interleukin-1β, interleukin-6, and tumor necrosis factor-α in Plce1(-/-) mice. In silico analysis of whole-exome sequences of 258 patients with Type A dissection identified 5 patients with non-synonymous PLCE1 variants. Our data suggest PLCε as a novel regulator in the development of TAAD and aortic insufficiency