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Progressive iron accumulation and renal impairment are prominent in both patients and mouse models of sickle cell disease (SCD). Endothelin A receptor (ETA) antagonism prevents this iron accumulation phenotype and reduces renal iron deposition in the proximal tubules of SCD mice. To better understand the mechanisms of iron metabolism in the kidney and the role of the [ET.sub.A] receptor in iron chelation and transport, we studied renal iron handling in a nonsickle cell iron overload model, heme oxygenase-1 ([Hmox-1.sup.-/-]) knockout mice. We found that [Hmox-1.sup.-/-] mice had elevated plasma endothelin-1 (ET-1), cortical ET-1 mRNA expression, and renal iron content compared with [Hmox-1.sup.+/+] controls. The [ET.sub.A] receptor antagonist, ambrisentan, attenuated renal iron deposition, without any changes to anemia status in Hmox-1mice. This was accompanied by reduced urinary iron excretion. Finally, ambrisentan had an important iron recycling effect by increasing the expression of the cellular iron exporter, ferroportin-1 (FPN-1), and circulating total iron levels in [Hmox-1.sup.-/-] mice. These findings suggest that the ET-1/[ET.sub.A] signaling pathway contributes to renal iron trafficking in a murine model of iron overload. Keywords: endothelin-1, iron homeostasis, ferroportin-1, sickle cell disease L'accumulation progressive de fer et l'insuffisance renale progressive se retrouvent de maniere proeminente chez les patients atteints d'anemie falciforme (AF) comme dans les modeles de la maladie chez la souris. L'antagonisme des recepteurs de l'endotheline A (ETA) permet de prevenir ce phenotype d'accumulation de fer et d'attenuer le depot de fer au niveau des tubules proximaux des reins de souris AF. Afin de mieux comprendre les modes d'action du metabolisme du fer dans les reins et le role des recepteurs [ET.sub.A] dans la chelation et le transport du fer, nous avons etudie la gestion du fer renal dans un modele de surcharge en fer sans AF : la souris << knock-out >> heme oxygenase 1 ([Hmox-1.sup.-/-]). Nous avons observe que la souris [Hmox-1.sup.-/-] presentait des taux plasmatiques d'endotheline 1 (ET-1), une expression corticale d'ET-1 en ARNm et des taux de fer dans les reins plus eleves que les temoins [Hmox-1.sup.+/+]. L'ambrisentane, un antagoniste des recepteurs ETA, permettait d'attenuer le depot de fer dans les reins sans aucune modification de l'etat anemique des souris [Hmox-1.sup.-/-], ce qui s'accompagnait d'une diminution de l'excretion urinaire du fer. Enfin, l'ambrisentane avait un important effet de recyclage du fer par l'entrainement d'un accroissement de l'expression de la ferroportine 1 (FPN-1), un exportateur de fer cellulaire, de meme que des taux de fer en circulation chez les souris [Hmox-1.sup.-/-]. Ces resultats laissent entendre que la voie de signalisation ET-1/ETA participerait au trafic du fer renal dans un modele de surcharge en fer chez la souris. Mots-cles : endotheline-1, homeostasie du fer, ferroportine 1, anemie falciforme, Introduction Iron homeostasis is fundamental for physiological processes in the body, and its imbalance has severe health consequences. Thus, iron metabolism is tightly regulated at the systemic and cellular levels. [...]

Aim: We aimed to test the hypothesis that a high‐salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)‐dependent mechanism. Methods: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L‐NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. Results: We found HS‐induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS‐275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS‐fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma‐derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG‐SOD and PEG‐catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. Conclusion: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling. [ABSTRACT FROM AUTHOR]

Behavior and function of living systems are synchronized by the 24-h rotation of the Earth that guides physiology according to time of day. However, when behavior becomes misaligned from the light-dark cycle, such as in rotating shift work, jet lag, and even unusual eating patterns, adverse health consequences such as cardiovascular or cardiometabolic disease can arise. The discovery of cell-autonomous molecular clocks expanded interest in regulatory systems that control circadian physiology including within the kidney, where function varies along a 24-h cycle. Our understanding of the mechanisms for circadian control of physiology is in the early stages, and so the present review provides an overview of what is known and the many gaps in our current understanding. We include a particular focus on the impact of eating behaviors, especially meal timing. A better understanding of the mechanisms guiding circadian function of the kidney is expected to reveal new insights into causes and consequences of a wide range of disorders involving the kidney, including hypertension, obesity, and chronic kidney disease. [ABSTRACT FROM AUTHOR]

Renal nerves have been an attractive target for interventions aimed at lowering blood pressure; however, the specific roles of renal afferent (sensory) versus efferent sympathetic nerves in mediating hypertension are poorly characterized. A number of studies have suggested that a sympathoexcitatory signal conveyed by renal afferents elicits increases in blood pressure, whereas other studies identified sympathoinhibitory afferent pathways. These sympathoinhibitory pathways have been identified as protective against salt-sensitive increases in blood pressure through endothelin B (ETB) receptor activation. We hypothesized that ETB-deficient (ETB-def) rats, which are devoid of functional ETBreceptors except in adrenergic tissues, lack appropriate sympathoinhibition and have lower renal afferent nerve activity following a high-salt diet compared with transgenic controls. We found that isolated renal pelvises from high salt-fed ETB-def animals lack a response to a physiological stimulus, prostaglandin E2, compared with transgenic controls but respond equally to a noxious stimulus, capsaicin. Surprisingly, we observed elevated renal afferent nerve activity in intact ETB-def rats compared with transgenic controls under both normal- and high-salt diets. ETB-def rats have been previously shown to have heightened global sympathetic tone, and we also observed higher total renal sympathetic nerve activity in ETB-def rats compared with transgenic controls under both normal- and high-salt diets. These data indicate that ETBreceptors are integral mediators of the sympathoinhibitory renal afferent reflex (renorenal reflex), and, in a genetic rat model of ETBdeficiency, the preponderance of sympathoexcitatory renal afferent nerve activity prevails and may contribute to hypertension. NEW & NOTEWORTHY Here, we found that endothelin B receptors are an important contributor to renal afferent nerve responsiveness to a high-salt diet. Rats lacking endothelin B receptors have increased afferent nerve activity that is not responsive to a high-salt diet. [ABSTRACT FROM AUTHOR]

Environmental cues such as light and timing of food intake influence molecular clocks that produce circadian rhythmicity of many biological functions. The master circadian clock is entrained by light input and synchronizes with peripheral clocks in every organ of the body. Careers that require rotating shift work schedules predispose workers to a constant desynchronization of these biological clocks and are associated with increased risk of cardiovascular disease. We used a stroke-prone spontaneously hypertensive rat model exposed to a known biological desynchronizer, chronic environmental circadian disruption (ECD), to test the hypothesis that it would accelerate the time to stroke onset. We then investigated whether time-restricted feeding could delay stroke onset and evaluated its usefulness as a countermeasure when combined with the constant disruption of the light cycle. We found that phase advancing of the light schedule accelerated stroke onset. Restricting food access time to 5 h/day regardless of lighting profoundly delayed stroke onset in both standard 12-h:12-h light/dark or ECD-lighting conditions compared with ad libitum feeding; however, acceleration by ECD versus control lighting conditions was still observed. Since hypertension is a precursor to stroke in this model, we assessed blood pressure in a small cohort longitudinally using telemetry. Mean daily systolic and diastolic blood pressure increased in a similar manner across rats in control and ECD conditions, thus hypertension was not grossly accelerated to cause earlier strokes. However, we observed intermittent dampening of rhythms after each shift of the light cycle reminiscent of a relapsingremitting nondipping state. Our results suggest that constant disruption of environmental rhythms may be associated with an increased risk of cardiovascular complications in the presence of cardiovascular risk factors. NEW & NOTEWORTHY This stroke-prone spontaneously hypertensive rat model significantly delayed stroke onset with the timed food restriction intervention. Blood pressure recordings in this same model were continuous through the 3 mo and showed dampened systolic rhythms after each shift in the lighting schedule. [ABSTRACT FROM AUTHOR]