Seasonal and nutritional changes in the short form of the leptin receptor expression and VEGF system in the choroid plexus, arcuate nucleus, and anterior pituitary in MTS-leptin and resistin-treated sheep

The short form of the leptin receptor (LeptRa) plays a key role in the transport of leptin to the central nervous system (CNS). Here, MTS-leptin and recombinant ovine (ro) leptin-mediated expression of LeptRa and VEGFA and VEGFR2 concentration in selected hypothalamic nuclei, choroid plexus (ChP), and anterior pituitary (AP) were analyzed considering the photoperiod and acute-fasting (experiment 1), and nutritional status (experiment 2) of ewes. In experiment 1, 60 sheep were fed normally or fasted for 72 h and received one injection of saline, MTS-leptin, or roleptin 1 h prior to euthanasia. LeptRa mRNA transcript levels and VEGF system protein concentrations were detected in the ARC, ChP predominantly in the SD, and AP for the LD without detection of LeptRa in the POA and VMH/DMH. In experiment 2, an altered diet for 5 months created lean or fat sheep. Twenty sheep were divided into four groups: the lean and fat groups were given saline, while the lean-R and fat-R groups received resistin 1 h prior to euthanasia. Changes in adiposity influenced the lowering effect of resistin on the expression of LeptRa and VEGF system protein concentrations. Overall, both photoperiodic and nutritional signals influence the effects of MTS-leptin/roleptin and resistin-mediated leptin transport to the CNS via LeptRa. Resistin seems to be another adipokine involved in the adaptive/pathological phenomenon of leptin resistance in sheep

Indoxyl Sulfate Promotes Arterial Thrombosis in Rat Model via Increased Levels of Complex TF/VII, PAI-1, Platelet Activation as Well as Decreased Contents of SIRT1 and SIRT3

Patients suffering from chronic kidney disease (CKD) are at a 20-fold higher risk of dying due to cardiovascular diseases (CVDs), primarily thrombosis following vascular injury. CKD is connected with retention of uremic toxins, especially indoxyl sulfate (IS), which are currently considered as a non-classical CKD-specific risk factor for CVDs. The present study aimed to examine the effect of chronic exposure to IS on the hemostatic system and arterial thrombosis in a model without greater interferences from the uremic milieu consisting of additional uremic toxins. Forty-eight male Wistar Crl:WI (cmdb) rats were divided into three groups: one control group and two experimental groups, which were exposed to 100 or 200 mg/kg of b.w./day of IS in drinking water for a period of 28 days. The control group received water without IS. At the end of the experiment, the induction of arterial thrombosis was performed. We investigated the impact of IS on thrombosis incidence, kinetics and strength of clot formation, platelet activity, aortic contents of sirtuin (SIRT) 1 and sirtuin 3 (SIRT3), hemostatic system, cardiorespiratory parameters, biochemistry of plasma and urine as well as histology of the thrombus, kidney, and liver. Obtained data revealed that chronic exposure to IS promotes arterial thrombosis via increased levels of complex tissue factor/factor VII, plasminogen activator inhibitor-1 (PAI-1), platelet activation, as well as decreased aortic levels of SIRT1 and SIRT3. Therefore, we hypothesize that IS enhances primary hemostasis leading to augmented formation of platelet plug with increased amounts of fibrin and affects secondary hemostasis through the influence on plasma coagulation and fibrinolysis factors, which results in the increased kinetics and strength of clot formation. The findings described may contribute to a better understanding of the mechanisms leading to increased thrombotic events in patients with CKD with elevated levels of IS

Adaptive Modifications of Maternal Hypothalamic-Pituitary-Adrenal Axis Activity during Lactation and Salsolinol as a New Player in this Phenomenon

Both basal and stress-induced secretory activities of the hypothalamic-pituitary-adrenal (HPA) axis are distinctly modified in lactating females. On the one hand, it aims to meet the physiological demands of the mother, and on the other hand, the appropriate and stable plasma cortisol level is one of the essential factors for the proper offspring development. Specific adaptations of HPA axis activity to lactation have been extensively studied in several animal species and humans, providing interesting data on the HPA axis plasticity mechanism. However, most of the data related to this phenomenon are derived from studies in rats. The purpose of this review is to highlight these adaptations, with a particular emphasis on stress reaction and differences that occur between species. Existing data on breastfeeding women are also included in several aspects. Finally, data from the experiments in sheep are presented, indicating a new regulatory factor of the HPA axis—salsolinol—which typical role was revealed in lactation. It is suggested that this dopamine derivative is involved in both maintaining basal and suppressing stress-induced HPA axis activities in lactating dams

Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes

Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups (n = 5): the lean and fat groups were administered with saline (Lean and Fat), while the Lean-R (Lean-Resistin treated) and Fat-R (Fat-Resistin treated) groups received recombinant bovine resistin. Plasma was assayed for LH, FSH, PRL, RSTN, leptin, GH, glucose, insulin, total cholesterol, nonesterified fatty acid (NEFA), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Expression levels of a suppressor of cytokine signaling (SOCS-3) and the long form of the leptin receptor (LRb) were determined in selected brain regions, such as the anterior pituitary, hypothalamic arcuate nucleus, preoptic area and ventro- and dorsomedial nuclei. The results indicate long-term alterations in body weight affect RSTN-mediated effects on metabolic and reproductive hormones concentrations and the expression of leptin signaling components: LRb and SOCS-3. This may be an adaptive mechanism to long-term changes in adiposity during the state of long-day leptin resistance

The Uremic Toxin Indoxyl Sulfate Accelerates Thrombotic Response after Vascular Injury in Animal Models

Chronic kidney disease (CKD) patients are at high risk for thrombotic events. Indoxyl sulfate (IS) is one of the most potent uremic toxins that accumulates during CKD. Even though IS is associated with an increased risk for cardiovascular disease, its impact on thrombotic events still remains not fully understood. The purpose of the study was to evaluate the direct effect of IS on thrombotic process. We examined the impact of acute exposure to IS on thrombus development induced by electric current in Wistar rats, intravital thrombus formation after laser-induced injury in the mice endothelium, coagulation profile, clot formation dynamics, platelet aggregations, and erythrocyte osmotic resistance. IS doses: 10, 30 and 100 mg/kg body weight (b.w.) increased weight of thrombus induced by electric current in dose-dependent manner (p < 0.001). Furthermore, two highest IS doses increased laser-induced thrombus formation observed via confocal system (increase in fluorescence intensity and total thrombus area (p < 0.01)). Only the highest IS dose decreased clotting time (p < 0.01) and increased maximum clot firmness (p < 0.05). IS did not affect blood morphology parameters and erythrocyte osmotic resistance, but augmented collagen-induced aggregation. Obtained data indicate that IS creates prothrombotic state and contributes to more stable thrombus formation. Thus, we concluded that IS may be one of crucial uremic factors promoting thrombotic events in CKD patients