Localization of natriuretic peptide receptors A, B, and C in healthy and diseased mouse kidneys

The natriuretic peptides (NPs) ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mediate their widespread effects by activating the natriuretic peptide receptor-A (NPR-A), while C-type natriuretic peptide (CNP) acts via natriuretic peptide receptor-B (NPR-B). NPs are removed from the circulation by internalization via the natriuretic peptide clearance receptor natriuretic peptide receptor-C (NPR-C). In addition to their well-known functions, for instance on blood pressure, all three NPs confer significant cardioprotection and renoprotection. Since neither the NP-mediated renal functions nor the renal target cells of renoprotection are completely understood, we performed systematic localization studies of NP receptors using in situ hybridization (RNAscope) in mouse kidneys. NPR-A mRNA is highly expressed in glomeruli (mainly podocytes), renal arterioles, endothelial cells of peritubular capillaries, and PDGFR-receptor β positive (PDGFR-β) interstitial cells. No NPR-A mRNA was detected by RNAscope in the tubular system. In contrast, NPR-B expression is highest in proximal tubules. NPR-C is located in glomeruli (mainly podocytes), in endothelial cells and PDGFR-β positive cells. To test for a possible regulation of NPRs in kidney diseases, their distribution was studied in adenine nephropathy. Signal intensity of NPR-A and NPR-B mRNA was reduced while their spatial distribution was unaltered compared with healthy kidneys. In contrast, NPR-C mRNA signal was markedly enhanced in cell clusters of myofibroblasts in fibrotic areas of adenine kidneys. In conclusion, the primary renal targets of ANP and BNP are glomerular, vascular, and interstitial cells but not the tubular compartment, while the CNP receptor NPR-B is highly expressed in proximal tubules. Further studies are needed to clarify the function and interplay of this specific receptor expression pattern

Prolyl‐4‐hydroxylases 2 and 3 control erythropoietin production in renin‐expressing cells of mouse kidneys

Activation of the hypoxia-signalling pathway induced by deletion of the ubiquitin-ligase von Hippel–Lindau protein causes an endocrine shift of renin-producing cells to erythropoietin (EPO)-expressing cells. However, the underlying mechanisms have not yet been investigated. Since oxygen-regulated stability of hypoxia-inducible transcription factors relevant for EPO expression is dependent on the activity of prolyl-4-hydroxylases (PHD) 2 and 3, this study aimed to determine the relevance of different PHD isoforms for the EPO expression in renin-producing cells in vivo. For this purpose, mice with inducible renin cell-specific deletions of different PHD isoforms were analysed. Our study shows that there are two subgroups of renal renin-expressing cells, juxtaglomerular renin+ cells and platelet-derived growth factor receptor-β+ interstitial renin+ cells. These interstitial renin+ cells belong to the cell pool of native EPO-producing cells and are able to express EPO and renin in parallel. In contrast, co-deletion of PHD2 and PHD3, but not PHD2 deletion alone, induces EPO expression in juxtaglomerular and hyperplastic renin+ cells and downregulates renin expression. A strong basal PHD3 expression in juxtaglomerular renin+ cells seems to prevent the hypoxia-inducible transcription factor-2-dependent phenotype shift into EPO cells. In summary, PHDs seem important for the stabilization of the juxtaglomerular renin cell phenotype. Moreover, these findings reveal tubulointerstitial cells as a novel site of renal renin expression and suggest a high endocrine plasticity of these cells. Our data concerning the distinct expression patterns and functions of PHD2 and PHD3 provide new insights into the regulation of renin-producing cells and highlight the need for selective PHD inhibitors

36th International Meeting of Sedimentology June 12–16, 2023 • Dubrovnik, Croatia

During the Eocene period, shallow-water carbonate systems were significantly influenced by climate fluctuations. Following the peak temperatures of the Early Eocene Climatic Optimum (EECO), a general cooling trend began, with short-lived (< 200 Kyr) warming events occurring alongside it. During the early Bartonian (around 40.1 Ma), a warming event known as the Middle Eocene Climatic Optimum (MECO) occurred, lasting approximately 500,000 years. In this scenario the types and calcification rates of marine organisms such as corals and larger benthic foraminifera (LBZ) were significantly impacted by the influence of global CO2 and oceanographic changes, which had a major effect on photic carbonate factories. To better understand the effects of these factors on carbonate factories, a detailed study of shallow-water facies types, distributions, and evolution was conducted. The Middle Eocene Monte Saraceno sequence, located on the eastern margin of the Apulia Carbonate Platform (Gargano Promontory, southern Italy), was selected as an ideal case study to investigate the relationships between carbonate factory types and climatic changes. This study identified two distinct intervals with different carbonate production, separated by a clear, sharp boundary. The lower interval consists of clinostratified thick beds of rudstone to floatstone, mostly made up of various large Nummulites tests, indicating an uppermost Lutetian to early Bartonian age (Shallow Benthic Zone 16–17). In contrast, the upper interval consists of coral floatstone to rudstone with a packstone matrix, rich in branching corals in association with gastropods, bivalves, and rare small LBF. The appearance of Heterostegina in this interval indicates a late Bartonian age (Shallow Benthic Zone 18). By integrating biostratigraphic and stable isotope data, the lower interval, mostly composed of Nummulites, was linked to the MECO and post-MECO intervals, during which higher global temperatures seemed to be tolerated by LBF, as occurred in the Early Eocene. However, the sharp transition to a coral-dominated carbonate factory during the late Bartonian could be attributed to a drop in temperature below the threshold for coral flourishment, rather than a simple facies shift caused by a relative sea-level drop

Influence of breast cancer risk factors and intramammary biotransformation on estrogen homeostasis in the human breast

Understanding intramammary estrogen homeostasis constitutes the basis of understanding the role of lifestyle factors in breast cancer etiology. Thus, the aim of the present study was to identify variables influencing levels of the estrogens present in normal breast glandular and adipose tissues (GLT and ADT, i.e., 17β-estradiol, estrone, estrone-3-sulfate, and 2-methoxy-estrone) by multiple linear regression models. Explanatory variables (exVARs) considered were (a) levels of metabolic precursors as well as levels of transcripts encoding proteins involved in estrogen (biotrans)formation, (b) data on breast cancer risk factors (i.e., body mass index, BMI, intake of estrogen-active drugs, and smoking) collected by questionnaire, and (c) tissue characteristics (i.e., mass percentage of oil, oil%, and lobule type of the GLT). Levels of estrogens in GLT and ADT were influenced by both extramammary production (menopausal status, intake of estrogen-active drugs, and BMI) thus showing that variables known to affect levels of circulating estrogens influence estrogen levels in breast tissues as well for the first time. Moreover, intratissue (biotrans)formation (by aromatase, hydroxysteroid-17beta-dehydrogenase 2, and beta-glucuronidase) influenced intratissue estrogen levels, as well. Distinct differences were observed between the exVARs exhibiting significant influence on (a) levels of specific estrogens and (b) the same dependent variables in GLT and ADT. Since oil% and lobule type of GLT influenced levels of some estrogens, these variables may be included in tissue characterization to prevent sample bias. In conclusion, evidence for the intracrine activity of the human breast supports biotransformation-based strategies for breast cancer prevention. The susceptibility of estrogen homeostasis to systemic and tissue-specific modulation renders both beneficial and adverse effects of further variables associated with lifestyle and the environment possible

Enhanced efficiency of a novel porous tip irrigated RF ablation catheter for pulmonary vein isolation

Irrigated tip radiofrequency (RF) catheter ablation is the most frequently used technology for pulmonary vein isolation (PVI). The purpose of this study was to compare the efficiency and the safety of 2 different open irrigated tip RF ablation catheters