Search

Histamine is involved in the immune response, vasodilation, neurotransmission, and gastric acid secretion. Although elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in renal disease, there is gap in knowledge regarding the mechanisms of histamine-related pathways in the kidney. We report here that all four histamine receptors, as well as enzymes responsible for metabolism of histamine are expressed in human and rat kidney tissues. In this study, we hypothesized that the histaminergic system plays a role in salt-induced kidney damage in Dahl Salt-Sensitive (DSS) rat, a model characterized with inflammation-driven renal lesions. To induce renal damage related to salt-sensitivity, DSS rats were challenged with a 21 days of high salt diet (HS, 4% NaCl); normal salt diet (NS, 0.4% NaCl) fed rats were used as a control. We observed lower histamine decarboxylase (HDC), and higher histamine N-methyltransferase (HNMT) levels in HS diet-fed rats, indicative of a shift in the histaminergic tone; metabolomics showed higher histamine and histidine levels in the kidneys HS diet-fed rats, while plasma levels for both compounds were lower. Acute systemic inhibition of histamine receptor 2 (HR2) in the DSS rat revealed that it lowered vasopressin receptor 2 and AQP2 abundance in the kidney. In summary, we established here the existence of the local histaminergic system, revealed a shift in the renal histamine balance during salt-induced kidney damage, and provided evidence that blockage of HR2 in the DSS rat affects water balance and urine concentrating mechanisms.

Environmental heterogeneity is an important driver of ecological communities. Here, we assessed the effects of local and landscape spatial environmental heterogeneity on ant community structure in temperate semi-natural upland grasslands of Central Germany. We surveyed 33 grassland sites representing a gradient in elevation and landscape composition. Local environmental heterogeneity was measured in terms of variability of temperature and moisture within and between grasslands sites. Grassland management type (pasture vs. meadows) was additionally included as a local environmental heterogeneity measure. The complexity of habitat types in the surroundings of grassland sites were used as a measure of landscape environmental heterogeneity. As descriptors of ant community structure, we considered species composition, community evenness, and functional response traits. We found that extensively grazed pastures and within-site heterogeneity in soil moisture at local scale, and a high diversity of land cover types at the landscape scale affected ant species composition by promoting nest densities. Ant community evenness was high in wetter grasslands with low within-site variability in soil moisture and surrounded by a less diverse landscape. Fourth-corner models revealed that ant community structure response to environmental heterogeneity was mediated mainly by worker size, colony size, and life history traits related with colony reproduction and foundation. We discuss how within-site local variability in soil moisture and low intensity grazing promote ant species densities, and highlight the role of habitat temperature and humidity affecting on community evenness. We hypothesize that a higher diversity of land cover types in a forest-dominated landscape buffers less favorable environmental conditions for ant species establishment and dispersal between grasslands. We conclude that spatial environmental heterogeneity at local and landscape scale plays an important role as deterministic force in filtering ant species and, along with neutral processes (e.g. stochastic colonization), in shaping ant community structure in temperate semi-natural upland grasslands.

Within the research project RUINS we assess the risk of inland floods of the Krummhörn region at the German North Sea coast. One third of this area lies below mean sea level, which demands to drain inland water during low tides by sluicing or otherwise by pumping. If, at any point in time, the drainage demand exceeds the drainage capacity, the available storage in polders and canals will be filled. Once this storage capacity is exceeded inland floods will occur.Previous risk assessment for such inland floods assumed a constant daily drainage capacity, which results from the installed pump capacity. We analysed process data provided by the operator of the drainage system (1. Entwässerungsverband Emden) at sub hourly resolution. The recorded water levels within the canal system showed that under current conditions the maximum areal drainage capacity is usually limited by the flow capacity within the canal network. The capacity of the pumps is dependend on the gradient from canal to North Sea water level.Under increased tidal water levels in the North Sea (e.g. storm flood situations) the pumping capacity can drop below the canal flow capacity. In consequence the areal drainage capacity is variable and can become much smaller than the constant daily drainage capacity assumed in previous studies. Due to the predicted increase in mean sea level with climate change the area might face an increased risk of inland floods despite a situation of insignificant changes in predicted rainfall patterns.Instead of costly infrastructural improvements, we propose a forecast system i) to optimise the drainage capacity in foresight of short term extreme situations and ii) to enable preparation for inland floodings. The proposed system includes the inherent uncertainty of the analysed processes and predicts the magnitude of upcoming inland floods. Currently, we use synthetic data as drivers, but these shall be exchanged by available weather and tide level predictions. The forecast system is realized as online accessible app, providing an easy usable and understandable access point for the operator and the interested public.

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 μg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 μg/day) or vehicle via s.c. osmotic pumps. At the end of the HS challenge, both groups exhibited similar outcomes for GFR, heart weight, plasma electrolytes, BUN, and creatinine. Sacubitril exacerbated kidney hypertrophy, but did not affect levels of renal fibrosis. We also observed aggravated glomerular lesions and increased formation of protein casts in the sacubitril-treated animals compared to controls. Thus, in Dahl SS rats, administration of sacubitril without renin-angiotensin-system blockage had adverse effects on renal disease progression, particularly in regards to glomerular damage and protein cast formation. We can speculate that while ANP levels are increased because of neprilysin inhibition, there are off-target effects of sacubitril, which are detrimental to renal function in the SS hypertensive state.

Sex differences (biological distinctions between males and females) present a complex interplay of genetic, developmental, biological, and environmental factors. More and more studies are shedding light on the importance of sex differences in normal physiology and susceptibility to cancer, cardiovascular and renal conditions, and neurodegenerative diseases. This mini-review is devoted to the role of sex dimorphisms in renal function, with a focus on the distinctions between male and female mitochondria. Here, we cover the aspects of renal mitochondrial bioenergetics where sex differences have been reported to date, for instance, biogenesis, reactive oxygen species production, and oxidative stress. Special attention is devoted to the effects of sex hormones, such as estrogen and testosterone, on mitochondrial bioenergetics in the kidney in physiology and pathophysiology.

Diuretics and renin-angiotensin system blockers are often insufficient to control the blood pressure (BP) in salt-sensitive (SS) subjects. Abundant data support the proposal that the level of atrial natriuretic peptide may correlate with the pathogenesis of SS hypertension. We hypothesized here that increasing atrial natriuretic peptide levels with sacubitril, combined with renin-angiotensin system blockage by valsartan, can be beneficial for alleviation of renal damage in a model of SS hypertension, the Dahl SS rat. To induce a BP increase, rats were challenged with a high-salt 4% NaCl diet for 21 days, and chronic administration of vehicle or low-dose sacubitril and/or valsartan (75 μg/day each) was performed. Urine flow, Na+ excretion, and water consumption were increased on the high-salt diet compared with the starting point (0.4% NaCl) in all groups but remained similar among the groups at the end of the protocol. Upon salt challenge, we observed a mild decrease in systolic BP and urinary neutrophil gelatinase-associated lipocalin levels (indicative of alleviated tubular damage) in the valsartan-treated groups. Sacubitril, as well as sacubitril/valsartan, attenuated the glomerular filtration rate decline induced by salt. Alleviation of protein cast formation and lower renal medullary fibrosis were observed in the sacubitril/valsartan- and valsartan-treated groups, but not when sacubitril alone was administered. Interestingly, proteinuria was mildly mitigated only in rats that received sacubitril/valsartan. Further studies of the effects of sacubitril/valsartan in the setting of SS hypertension, perhaps involving a higher dose of the drug, are warranted to determine if it can interfere with the progression of the disease.

Determining the effects of local and landscape drivers on endangered species and predicting potential suitable habitats for their persistence is crucial for effective conservation management. Here, we applied a multi-scale approach to disentangle the effects of host resources, local, and landscape variables on the occurrence pattern of Phengaris (= Maculinea) nausithous in semi-natural upland grasslands. Our approach comprised the assessment of host parameters (plant cover, density, height, flower heads density, ant nest density, ant colony size), local grassland management (pasture, meadow), site conditions (area, shape, terrain attributes), and landscape variables (landscape composition, connectivity). We used ensemble of small models based on bivariate generalized linear models for explaining and predicting the butterfly occurrence pattern. Bivariate models revealed that host ant nest density, plant cover and height, local grassland management type (pasture), slope and eastness, landscape forest cover and grassland connectivity had a positive effect on the occurrence of P. nausithous (average explained deviance 20.5%). Host ant density, host plant cover, and local grassland management were the most influential factors on the ensemble predictions. The presence of P. nausithous in upland grasslands is not only determined by host resources, but also by local and landscape factors. Such factors proved to be relevant for identifying and predicting suitable grassland sites for this endangered species. Consequently, we recommend that conservation actions should include a landscape perspective to promote connectivity by facilitating coherent grazing networks enabling dispersal between semi-natural upland grasslands and thus species persistence.

Die vorliegende Arbeit erforscht negative Effekte von Stigma in einer bev��lkerungsbasierten Gruppe mit mild ausgepr��gten psychischen Symptomen. Die Ergebnisse legen nahe, dass negative Effekte von Stigma eine gr����ere Gruppe betreffen als bisher angenommen. Insbesondere werden negative Auswirkungen aufgezeigt (zum Beispiel sozialer R��ckzug und Geheimhaltung), welche das Risiko der sozialen Isolation erh��hen. Daher sind effektive Ma��nahmen gegen Stigma n��tig, die sowohl die vermeintlich ���gesunde��� ��ffentlichkeit und ihre verbreiteten Ansichten und Haltungen als auch Individuen mit unterschwelligen psychiatrischen Erkrankungen einbeziehen. Anhand einer repr��sentativen Bev��lkerungsumfrage (basierend auf Selbstbeantwortung von 676 Teilnehmern mit erh��hten psychischen Symptomen) wurden Resilienz, Stigma- Variablen, Scham aufgrund einer psychischen Erkrankung, sowie vermeidende Bew��ltigungsmechanismen (Geheimhaltung und Sozialer R��ckzug) erfasst. In einem Pfadmodell wurden Stigma-Variablen und Resilienz als Pr��diktoren f��r vermeidende Bew��ltigungsmechanismen untersucht. Erh��hter Stigma-Stress l��sst sich durch niedrigere Resilienz, mehr wahrgenommenes Stigma, st��rkere Gruppenidentifikation und st��rkere wahrgenommene Legitimit��t von Diskriminierung vorhersagen. Ein erh��htes Schamgef��hl ist ebenfalls verbunden mit mehr wahrgenommener Legitimit��t von Diskriminierung. Niedrigere Resilienz, st��rker wahrgenommenes Stigma, st��rkere Gruppenidentifikation und mehr wahrgenommene Legitimit��t erh��hen vermeidende Bew��ltigungsmechanismen auf Stigma. Stigma-Stress mediiert teilweise bei Effekten von Resilienz, wahrgenommenem Stigma und Gruppenidentifikation auf vermeidende Bew��ltigungsmechanismen. Schamgef��hl mediiert teilweise bei Effekten von wahrgenommener Legitimit��t auf Bew��ltigung. Stigma- Stress und Schamgef��hl korrelieren direkt positiv mit vermeidende Bew��ltigungsmechanismen. Negative Effekte von Stigma k��nnen zu erh��hter Geheimhaltung und sozialem R��ckzug bei Mitgliedern der Allgemeinbev��lkerung mit erh��hten psychischen Symptomen f��hren. Diese vermeidenden Bew��ltigungsreaktionen haben vermutlich sch��dliche Auswirkungen, die potenziell zur Verst��rkung von vorbestehenden psychischen Leiden und sozialer Abschottung f��hren. Die Ergebnisse unterstreichen die Notwendigkeit, erstens Stigma in der ��ffentlichkeit zu reduzieren und zweitens betroffene Individuen bei ihren Bew��ltigungsmechanismen von Stigma und Scham zu unterst��tzen.

Background: Atrial natriuretic peptide ( ANP) is a hormone produced primarily in the heart, which induces vasodilation and natriuresis. We showed previously that a knockout of ANP in Dahl SS rat results in hypertension and HFpEF phenotype. There is a gap in knowledge regarding the role of inflammation and mitochondrial function in HFpEF that accompanies SSH. We hypothesize that the ANP deficiency in SSH leads to pressure overload, which affects cardiac inflammation and mitochondrial function. Methods: At 8 weeks of age, male wild type (SS WT ) and Nppa knockout (ANP knockout, SS Nppa-/- ) Dahl SS rats were placed on normal salt ( NS , 0.4% NaCl) or a high salt ( HS , 4% NaCl) for 21 days. Tissues were harvested for histological and Western analysis. TEM was used to obtain electron micrographs. EPR spectroscopy was performed in snap-frozen tissues post injection of POBN. 2-way ANOVA was employed for statistical comparison. Results: Heart-to-body-weight ratio was higher in SS Nppa-/- rats (pp Nppa-/- rats displayed increases in cardiac fibrosis following HS diet ( p Nppa-/- hearts exhibit a trend for increased lipid peroxidation compared to SS WT . Cardiac cytokine profile demonstrated an increase in IL-1α, IL-1β, L-6, IL-17, TNF-α, sICAM-1, MIP-1α, MIP-3α, in the SS WT rats fed a HS diet vs NS diet, and lower levels of these in the HS-diet fed SS Nppa-/- rats vs SS WT . HS diet was sufficient to induce increases in mitochondrial area ( p p 0.001), and overall health score ( p WT and SS Nppa-/- rats, but no genotype-specific differences were reported. We observed changes in fission/fusion proteins: Opa1 expression was elevated in SS Nppa-/- vs SS WT ( p p Conclusions: Although SS Nppa-/- rats develop a HFpEF phenotype, exacerbated cardiac fibrosis and higher lipid peroxidation vs SS WT rats, inflammation and overall mitochondrial damage are diminished in the hearts of these animals at day 21 of the HS diet. Further studies are needed to elucidate the mechanisms by which inflammation may affect the development of HFpEF during SS hypertension in a cell-specific and time-dependent manner.

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from high salt intake can be partially associated with a lower level of the atrial natriuretic peptide (ANP). In plasma, ANP is quickly degraded by neprilysin; therefore, pharmacological inhibition of this metalloprotease (f.i. with sacubitril) can increase ANP level. We have shown earlier that lower dose of sacubitril in combination with valsartan (75 μg/day) has beneficial effects on renal function in SS hypertension. The goal of this study was to evaluate the effects of sacubitril administered at a higher dose on renal damage of Dahl SS rats. Sacubitril (125 μg/day) or vehicle were administered to male Dahl SS rats (Charles River) via s.c. osmotic pumps. To induce hypertension, both groups were fed a purified 4% NaCl diet (HS, Dyets Inc) for 21 days. Glomerular filtration rate (GFR, FITC-inulin) and BP (tail cuff) values were obtained before and after the HS challenge. Data was analyzed with 1-way ANOVA. When compared to vehicle treated rats, 125 μg/day of sacubitril insignificantly increased systolic BP measured at the end of the 21-day HS challenge; no changes in GFR, heart weight, plasma electrolytes, BUN and creatinine were observed. However, sacubitril caused kidney hypertrophy (two kidneys to body weight: 8.8±0.4 vs 10.4±0.4 mg/g, p=0.04,), but did not affect renal medullary of cortical fibrosis. We also observed aggravated glomerular lesions in the sacubitril-treated animals compared to controls (glomerular injury score: 1.6±0.02 vs 0.9±0.08 au, p=0.034), and increased formation of protein casts (1.8±0.3 vs 1.3±0.2 au, p=0.034). Thus, in Dahl SS rats, administration of sacubitril at 125 μg/day had adverse effects on renal disease progression, especially glomerular damage and protein casts formation. In our prior study we showed that the combination of sacubitril at 75 μg/day with the angiotensin receptor blocker (ARB), valsartan, is effective to alleviate these outcomes. It is likely that the inhibition of neprilysin by sacubitril results in accumulation of Ang II and/or bradykinin and/or RAAS activation, which masks the beneficial effects of ANP level increase.

There are clinical data suggesting that low levels of Atrial Natriuretic Peptide (ANP) aggravate susceptibility to salt-sensitive (SS) hypertension. ANP is known to affect mitochondria in many tissues, however, little is known about the effects of ANP on renal mitochondrial function. According to our earlier studies, Dahl SS rats lacking ANP exhibit increased blood pressure and pronounced kidney injury. We hypothesized that in SS hypertension ANP deficiency affects renal mitochondrial bioenergetics and contributes to renal function impairment. SS hypertension was induced in male SS NPPA-/- ( Nppa knockout in Dahl SS background, KO) and SS WT (wild type, WT) rats by a high salt (HS) 4% NaCl diet administered for 21 days. Age-matched control animals were fed a normal (NS) 0.4% NaCl salt diet. A combination of in vivo studies, molecular biology and tests of mitochondria isolated from renal cortex (seahorse respiration and spectrofluorimetry assays using TMRM, Amplex Red and MCLA) were used to probe the role ANP in mitochondrial function. Data was analyzed with ANOVA followed by Holm-Sidak post hoc. We report a significant decrease in mitochondrial membrane potential in the SS NPPA-/- rats vs SS WT (25 ± 4% decrease in KO vs WT on NS, and a 16 ± 5% decrease in KO on HS). Furthermore, mitochondrial H 2 O 2 (57.7 ± 7.4 (WT) vs 57.6 ± 1.3 au (KO), pNPPA-/- rats on HS diet in comparison with SS WT , and increased SOD2 levels were observed in the KO animals. Furthermore, SS NPPA-/- rats exhibit higher MCU (mitochondrial calcium uniporter) activity than SS WT , implying an ANP-dependent effect on mitochondrial calcium influx. Seahorse assay revealed dramatic elevation of the basal, ATP-linked, maximal and spare oxygen consumption rate (OCR) in the cortical mitochondria of the knockout rats on HS, while in HS fed SS WT rats these OCR parameters were, as expected, reduced (vs NS). Therefore, deficiency of circulating ANP leads to significant changes of renal mitochondrial bioenergetics, potentially via effects on mitochondrial calcium uptake, which in turn affects respiratory chain activity leading to oxidative stress.

Adaptation to environmental changes requires decision making under uncertainty. Providing forecasts of the potential impact of different management options is a common task for environmental modellers. However, we rarely succeed in conveying uncertainties as relevant information to distinguish management options regarding their expected value and its uncertainty. Quite to the contrary, the reality in the modelling of complex systems under climate change often leads to similar mean values and broad uncertainty bands. Both may irritate users and even lead to indecision and inaction despite an urgent call for action.In the inter- and transdisciplinary project RUINS (Risk, Uncertainty and Insurance under Climate Change. Coastal Land Management on the German North Sea), we address a region that is sensitive to changes in relative sea level, weather patterns and land-use practices. We develop methods to quantify the uncertainty of adaptation measures through the chain of models for climate, hydrology and landscape management. The aim is to provide tools for the evaluation of forecasted effects of management options, where uncertainty itself is considered an evaluation criterion.We will present examples to point out pitfalls and potentials of uncertainty quantification in environmental model forecasting for management decision making: (i) we highlight different sources and different kinds of uncertainty with an example of agricultural production; (ii) we address trade-offs between expected wind power production and the security of its provision; moreover, (iii) we highlight the role of temporal data resolution and capacity of drainage structures in the assessment of flood protection during extreme rain events.