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Background: 25-hydroxyvitamin D (25(OH)D) and potentially also 1,25-dihydroxyvitamin D (1,25(OH)2D) inhibits the synthesis of parathyroid hormone (PTH) in the chief cells of the parathyroid gland. Clinical studies showing a negative correlation between (25(OH)D and PTH are in good agreement with these findings in basic science studies. However, PTH was measured in these studies with the currently clinically used 2nd or 3rd generation intact PTH (iPTH) assay systems. iPTH assays cannot distinguish between oxidized forms of PTH and non-oxidized PTH. Oxidized forms of PTH are the by far most abundant form of PTH in the circulation of patients with impaired kidney function. Oxidation of PTH causes a loss of function of PTH. Given that the clinical studies done so far were performed with an PTH assay systems that mainly detect oxidized forms of PTH, the real relationship between bioactive non-oxidized PTH and 25(OH)D as well as 1,25(OH)2D is still unknown. Methods: To address this topic, we compared for the first time the relationship between 25(OH)D as well as 1,25(OH)2D and iPTH, oxPTH as well as fully bioactive n-oxPTH in 531 stable kidney transplant recipients in the central clinical laboratories of the Charité. Samples were assessed either directly (iPTH) or after oxPTH (n-oxPTH) was removed using a column that used antihuman oxPTH monoclonal antibodies, a monoclonal rat/mouse parathyroid hormone antibody (MAB) was immobilized onto a column with 500 liters of plasma samples. Spearman correlation analysis and Multivariate linear regression were used to evaluate the correlations between the variables. Results: There was an inverse correlation between 25(OH)D and all forms of PTH, including oxPTH (iPTH: r=-0.197, p<0.0001; oxPTH: r=-0.203, p<0.0001; n-oxPTH: r=-0.146, p=0.001). No significant correlation was observed between 1,25(OH)2D and all forms of PTH. Multiple linear regression analysis considering age, PTH (iPTH, oxPTH and n-oxPTH), serum calcium, serum phosphor, serum creatinine, fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), albumin, and sclerostin as confounding factors confirmed these findings. Subgroup analysis showed that our results are not affected by sex and age. Conclusion: In our study, all forms of PTH are inversely correlated with 25- hydroxyvitamin D (25(OH)D). This finding would be in line with an inhibition of the synthesis of all forms of PTH (bioactive n-oxPTH and oxidized forms of PTH with minor or no bioactivity) in the chief cells of the parathyroid glad. [ABSTRACT FROM AUTHOR]

Abstract: The pathways leading to salt-sensitive hypertension and renal damage in rescued E[T.sub.B] receptor-deficient (ETBRd) rats are still unknown. The objective of the study was therefore to identify modifications of [...]

Abstract: We recently demonstrated that inhalation of the endothelin receptor A (E[T.sub.A]) antagonist LU 135252 improved arterial oxygenation and reduced pulmonary artery pressure in experimental acute lung injury (ALI). In [...]

Abstract: Activation of the endothelin (ET) system promotes vasoconstriction, inflammation, and fibrosis in various tissues, including the lung. Therefore, ET-1 transgenic mice overexpressing ET-1 develop pulmonary fibrosis in a slow, [...]

Abstract: Endothelin-1 (ET-1) exhibits potent proinflammatory and profibrotic properties. Moreover, inflammation is a potent stimulus for inducible NO synthase (iNOS), which has been shown to contribute to cardiac injury. We [...]

Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism.Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done.Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 ± 0.70% vs. 6.21 ± 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 ± 0.80%) compared to II mothers delivering boys (6.21 ± 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension.Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex. [ABSTRACT FROM PUBLISHER]

Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A1 receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A1 receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (236.5%, p<0.05), especially in those receiving furosemide (241.9%, p<0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p<0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A1 receptor antagonists are clinically beneficial at different stages of liver cirrhosis. [ABSTRACT FROM AUTHOR]

The pathways leading to salt-sensitive hypertension and renal damage in rescued ETB receptor-deficient (ETBRd) rats are still unknown. The objective of the study was therefore to identify modifications of urinary peptide and protein expression in ETBRd rats (n = 9) and wild-type controls (n = 6) using SDS - polyacrylamide gel electrophoresis (SDS-PAGE) and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology. Glomerular filtration rate, glomerulosclerosis, and tubulointerstitial fibrosis did not differ between the groups. ETBRd rats showed slightly higher blood pressure (p < 0.001), media/lumen ratio of intrarenal arteries (p < 0.01), and albuminuria (p < 0.01). SDS-PAGE confirmed albuminuria, but showed no differences in the urinary excretion of low molecular weight proteins (<60 kDa). SELDI-TOF-MS profiling revealed 9 proteomic features at molecular masses (Da) of 2720, 2980, 3130, 3345, 6466, 6682, 8550, 18 729, and 37 492, which were significantly elevated (p < 0.02) in urine of ETBRd rats. The results demonstrate that, independent of structural changes in the kidneys, ETB-receptor deficiency causes specific differences in urinary peptide and protein excretion. SELDI-TOF-MS may be a valuable tool for the characterization of urinary biomarkers helping to uncover the mechanism of ETBR action in the kidney. Les mécanismes menant à l’hypertension sensible au sel et à l’atteinte rénale chez les rats déficients en récepteurs B de l’endothéline (dRETB) demeurent inconnus. La présente étude a donc eu pour objectif d’identifier les modifications dans l’expression des protéines et des peptides urinaires chez les rats dRETB (n = 9) et chez des témoins de type sauvage (n = 6), en utilisant l’électrophorèse sur gel de polyacrylamide - SDS (PAGE-SDS) et la technologie de désorption/ionisation laser activée par une surface en spectrométrie de masse en temps de vol (SELDI-TOF-MS). Le taux de filtration glomérulaire, la glomérulosclérose et la fibrose tubulo-interstitielle n’ont pas différé entre les groupes. Les rats dRETB ont montré une légère augmentation de la pression artérielle (p < 0,001), du rapport média/lumière des artères intrarénales (p < 0,01) et de la protéinurie (p < 0,01). La PAGE-SDS a confirmé la protéinurie, mais n’a pas montré de différences dans l’excrétion urinaire des protéines de faible poids moléculaire (<60 kDa). L’analyse des profils par SELDI-TOF-MS a révélé 9 caractéristiques protéomiques à de masses moléculaires (Da) de 2720, 2980, 3130, 3345, 6466, 6682, 8550, 18729 et 37492, qui étaient significativement élevées (p < 0,02) dans l’urine des rats dRETB. Les résultats démontrent que la déficience en RETB induit des différences spécifiques dans l’excrétion des protéines et des peptides urinaires, indépendamment de toutes modifications de la structure rénale. La technologie SELDI-TOF-MS pourrait être un outil utile pour la caractérisation de biomarqueurs urinaires permettant d’identifier le mécanisme d’action des RETB dans le rein. [ABSTRACT FROM AUTHOR]

Activation of the endothelin (ET) system promotes vasoconstriction, inflammation, and fibrosis in various tissues, including the lung. Therefore, ET-1 transgenic mice overexpressing ET-1 develop pulmonary fibrosis in a slow, age-dependent manner. In vivo, NO is the most important counterregulatory mediator of the ET system and decreases ET-1 promoter activity. The aim of our study was to elucidate the impact on pulmonary inflammation and fibrosis of the interaction between NO and the ET system in young ET-1 transgenic mice before the onset of pulmonary fibrosis. Male ET-1 transgenic mice and wild-type littermates at the age of 8 weeks were randomly allocated to the following 6 groups: WT (n = 11), wild-type animals without treatment; WT + l-NAME (n = 14), wild-type animals receiving l-NAME, an inhibitor of NO synthase; WT + l-NAME + LU (n = 13), wild-type animals receiving l-NAME and LU 302872, a dual ETA/ETB-receptor antagonist; ET1tg (n = 10), ET-1 transgenic mice; ET1tg + l-NAME (n = 13); and ET1tg + l-NAME + LU (n = 13). After 6 weeks, animals were euthanized, and hearts and lungs were harvested for histology and immunohistochemistry. No differences in pulmonary inflammation, as indicated by macrophage infiltration, or in interstitial fibrosis were observed between WT and ET1tg mice at baseline; however, inflammation and interstitial fibrosis were significantly enhanced in ET1tg mice, but not in WT groups, after l-NAME treatment. The combined ETA/ETB-receptor antagonist LU 302872 abolished inflammation and interstitial fibrosis in l-NAME-treated ET1tg mice. Perivascular fibrosis and media/lumen ratio of pulmonary bronchi and arteries did not differ between all study groups. In our study l-NAME induced pulmonary fibrosis and inflammation only in young ET1tg mice. Additional treatment with LU 302872 abolished these effects. We thus conclude that an imbalance between an activated ET system and a suppressed NO system contributes to pulmonary inflammation and fibrosis. L’activation du système endothéline (ET) favorise la vasoconstriction, l’inflammation et la fibrose dans divers tissus, le poumon inclus. Ainsi, les souris transgéniques surexprimant l’ET-1 développent une fibrose pulmonaire lentement avec l’âge. In vivo, le NO est le principal médiateur de la contre-régulation du système ET, et il diminue l’activité promotrice de l’ET-1. La présente étude a eu pour but d’expliquer l’impact de l’interaction entre le NO et le système ET sur l’inflammation et la fibrose pulmonaires chez de jeunes souris transgéniques ET-1, avant l’apparition de la fibrose pulmonaire. Des souris transgéniques ET-1 mâles et des souris de type sauvage de même portée âgés de 8 semaines ont été réparties aléatoirement dans les groupes suivants : TS (n = 11) : animaux de type sauvage sans traitement; TS + l-NAME (n = 14) : animaux de type sauvage recevant l-NAME; TS + l-NAME + LU (n = 13) : animaux de type sauvage recevant l-NAME et LU 302872, un antagoniste des récepteurs ETA/ETB; ET1tg (n = 10); ET1tg + l-NAME (n = 13); ET1tg + l-NAME + LU (n = 13). Après 6 semaines, les animaux ont été sacrifiés, et les cœurs et poumons ont été prélevés et soumis à un examen histologique/immunohistochimique. Aucune différence dans l’inflammation pulmonaire - comme indiqué par l’infiltration des macrophages - ou dans la fibrose interstitielle n’a été observée entre les souris TS et ET1tg en condition basale. Toutefois, après le traitement avec l-NAME, l’inflammation et la fibrose interstitielle ont augmenté significativement chez les souris ET1tg, alors que cet effet n’a pas été noté chez les groupes TS. L’antagoniste des récepteurs ETA/ETB, LU 302872, a supprimé l’inflammation et la fibrose interstitielle chez les souris ET1tg traitées avec l-NAME. La fibrose périvasculaire et le rapport média/lumière des artères et des bronches pulmonaires ont été similaires chez tous les groupes. Dans notre étude, l-NAME a induit une fibrose et une inflammat [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) and endothelin-1 (ET-1) are known to play a major role in renal and vascular pathophysiology and exhibit a close interaction with ET-1, stimulating NO production; NO in turn inhibits ET-1 expression. Our objectives were (1) to establish a novel transgenic mouse model facilitating ET-1 expression assessment in vivo, (2) to validate this model by assessing prepro-ET-1 promoter activity in mice embryos by means of our novel model and comparing expression sites to well-established data on ET-1 in fetal development and (3) to investigate renal ET–NO interaction by assessing prepro-ET-1 promoter activity in different structures of the renal cortex in the setting of blocked NO synthases vial-NAME administration. We established transgenic mice carrying a lacZ reporter gene under control of the human prepro-ET-1 gene promoter sequence (8 kb of 5′ sequences). Bluo-Gal staining of tissue sections revealed intracellular blue particles as indicators of prepro-ET-1 promoter activity. In mouse embryos, we detected high prepro-ET-1 promoter activity in the craniofacial region, as well as in bone and cartilage consistent with the literature. In order to investigate the interaction of ET-1 and NO in the kidney in vivo, transgenic mice at the age of 3–4 months were treated with a single dose of the NO synthase inhibitorl-NAME (25 mg (kg bw)−1i.p.) 12 h before kidney removal. Bluo-Gal staining of kidney sections revealed intracellular blue particles as indicators of prepro-ET-1 promoter activity in tubular and vascular endothelium and glomerular cells. Particle count was closely correlated to kidney tissue ET-1 content ( R= 0.918, P < 0.001). Comparison of counts revealed an increase by 135 ± 53% inl-NAME treated ( n= 12) compared to non-treated mice ( n= 10, P= 0.001). Cell-type specific evaluation revealed an increase of 136 ± 51% in tubular ( P= 0.001) and 105 ± 41% in glomerular cells ( P= 0.046), but no significant increase in vascular endothelium. In conclusion, our study revealed a close interaction of renal endothelin and the NO system in a cell-type specific manner. Our new transgenic model provides a unique opportunity to analyse regulation of the ET system on a cellular level in vivo. [ABSTRACT FROM AUTHOR]

Aims: To assess the predictive value of estradiol (E2) related parameters on the incidence of gestational diabetes mellitus (GDM) in women undergoing fresh embryo transfer., Materials and Methods: A Post-hoc analysis of a prospective cohort study., Results: We identified an optimal E2/follicle (E2/F) ratio threshold of 246.03 pg/ml on the day of human chorionic gonadotropin (hCG) administration. Women with an E2/F ratio exceeding this threshold had significantly lower rates of GDM (12.75% vs. 20.41%, P < 0.001) and ovarian hyperstimulation syndrome (OHSS) (11.75% vs. 15.48%, P = 0.03). Additional E2 parameters were also evaluated: baseline E2, E2 on hCG day, E2 increase, and E2 fold change. Lower GDM rates were observed in women with baseline E2 above 31.50 pg/ml (13.51% vs. 19.42%, P <0.01), E2 on hCG day above 3794.50 pg/ml (12.26% vs. 19.32%, P < 0.001), and E2 increase above 3771.50 pg/ml (12.24% vs. 19.28%, P < 0.001). There were no significant differences in OHSS rates for these additional E2 parameters. After adjusting for confounders, lower E2/F ratio (OR: 1.626, 95% CI: 1.229-2.150, P <0.01), E2 on hCG day (OR: 1.511, 95% CI: 1.133-2.016, P = 0.01), and E2 increase (OR: 1.522, 95% CI: 1.141-2.031, P <0.01) were identified as risk factors for GDM., Conclusion: This study demonstrates that an E2/F ratio over 246.03 pg/ml is significantly associated with a reduced risk of both GDM and OHSS in women undergoing fresh embryo transfer, highlighting the E2/F ratio as a superior predictive biomarker compared to other E2-related parameters., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Liu, Xu, Hu, Cai, Gong, Lin, Kalk, Krämer and Hocher.)

Objectives: Our study tries to investigate the effect of the Mediterranean diet (MeDiet) on assisted reproductive treatment outcomes in women after COVID-19 infection., Design: A prospective observational cohort study in the Reproductive and Genetic Hospital of CITIC-Xiangya from February 2023 to August 2023.Subjects: A total of 605 participants previously infected with COVID-19 were enrolled., Exposure: None., Main Outcome Measurement: The primary outcomes are oocyte and embryo quality. The secondary outcomes are pregnancy outcomes., Results: A majority of participants ( n  = 517) followed low to moderate MeDiet, and only a small group of them ( n  = 88) followed high MeDiet. The blastocyst formation rate is significantly higher in MeDiet scored 8-14 points women (46.08%), compared to the other two groups (which is 41.75% in the low adherence population and 40.07% in the moderate adherence population respectively) ( p  = 0.044). However, the follicle number on hCG day, yield oocytes, normal fertilized zygotes, fertilization rate, day three embryos (cleavage embryos), and embryo quality are comparable among the three groups. For those who received embryo transfer, we noticed an obvious trend that with the higher MeDiet score, the higher clinical pregnancy rate (62.37% vs. 76.09% vs. 81.25%, p  = 0.197), implantation rate (55.84% vs. 66.44% vs. 69.23%, p  = 0.240) and ongoing pregnancy rate (61.22% vs. 75.00% vs. 81.25%, p  = 0.152) even though the p values are not significant. An enlarging sample size study, especially in a high adherence population should be designed to further verify the effects of MeDiet's role in improving IVF performance., Conclusion: High adherence to MeDiet is associated with improved blastocyst formation in women after COVID-19 infection. There is also a trend that high adherence to MeDiet might be beneficial to clinical pregnancy, embryo implantation as well as ongoing pregnancy in these women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Wang, Guo, Zhao, Lin, Hocher, Kalk, Wang and Gong.)

Introduction: Periostin is a matricellular protein. Elevated serum concentrations of periostin have been reported in patients with various cardiovascular diseases, including heart failure. Patients with end-stage renal disease have a substantially increased risk for cardiovascular diseases. However, there is a lack of clinical studies to clarify the prognostic significance of systemic periostin on all-cause mortality in patients with end-stage renal disease on hemodialysis., Methods: 313 stable end-stage renal disease patients were recruited and followed for 5 years concerning all-cause mortality. At baseline, we collected blood samples and clinical data. Serum periostin concentrations were measured using a certified ELISA., Results: The optimal cut-off value for serum periostin regarding all-cause mortality, calculated through receiver operating characteristic analysis, was 777.5 pmol/L. Kaplan-Meier survival analysis using this cut-off value demonstrated that higher periostin concentrations are linked to higher all-cause mortality (log-rank test: p = 0.002). Subgroup analysis revealed that serum periostin concentrations only affected all-cause mortality in male but not in female patients (p = 0.002 in male patients and p = 0.474 in female patients). Multivariate Cox regression analyses, adjusted for confounding factors, likewise showed that elevated serum periostin concentrations were positively associated with all-cause mortality in male (p = 0.028) but not in female patients on hemodialysis (p = 0.313)., Conclusion: Baseline serum periostin is an independent risk factor for all-cause mortality in male patients with chronic renal disease on hemodialysis., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure., Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested., Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50% in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67% mortality in vehicle-treated rats, but only 20% after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case)., Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.

Background: Transient tachypnea of the newborn (TTN) is the most common perinatal respiratory disorder. It was suggested that the pathogenesis of TTN might involve altered activity of female sex hormones. This study analyzed whether the PROGINS progesterone receptor polymorphism, which is less responsive to progesterone, is associated with TTN., Methods: A cohort of 2352 infants born to Caucasian women at the Obstetrics Department of the Charite was investigated prospectively. The collected information included the occurrence of respiratory disorders, birth weight, gestational age at delivery, mode of delivery, and maternal morbidity. Mothers and newborns were genotyped for the PROGINS progesterone receptor polymorphism. Statistical analyses considered correction for confounding factors., Results: The presence of the mutated T2-allele either in mothers or in infants was associated with a reduction of the incidence of TTN in a gene dose-dependent manner (mothers T1/T1: 6.6%, T1/T2: 4.3% T2/T2: 2.3%, p < 0.01; infants T1/T1: 6.5%, T1/T2: 4.7%, T2/T2: 0.0%, p = 0.02 in a multivariable regression model). The total number of mutated T2-alleles present in a mother/child pair was associated with a reduction of TTN (4 T2-alleles: 6.4%, n=95; 3: 5.9%, n=30; 2: 3.1%, n=9; 1: 1.4%, n=1; 0:0%, n=0; p < 0.01 in a multivariable regression model)., Conclusions: Both the maternal and fetal mutated alleles of the PROGINS progesterone receptor polymorphism seem to protect from TTN. The same phenotype occurs regardless of whether the mutation is localized in the mother or in the infant. Fetal as well as maternal T2-alleles synergistically reduce the risk for TTN in a gene dose-dependent manner.