Endothelin receptor B is Required for the Blood Pressure lowering Effect of G Protein-coupled Estrogen Receptor 1 in Ovariectomized Rats.

Activation of the G protein-coupled estrogen receptor 1 (GPER1) elicits antihypertensive actions in different animal models. The endothelin-1 signaling system plays a fundamental role in blood pressure regulation. Lack of functional endothelin receptor B receptors (ETB) evokes hypertension and salt sensitivity. GPER1 and ETB interact to promote urinary sodium excretion in female rats. We hypothesized that activation of GPER1 protects against hypertension and salt sensitivity induced by ETB antagonism in female rats. Female Sprague Dawley rats were implanted with radiotelemetry. Then, animals were subjected to ovariectomy and simultaneously implanted with minipumps to deliver either the GPER1 agonist, G1, or its corresponding vehicle (Veh). Two weeks post-surgery, we initiated treatment of rats with the ETB antagonist, A-192621. Animals were maintained on a normal salt (NS) diet then challenged with a high salt (HS) diet for an additional 5 days. Assessment of mean arterial blood pressure revealed an increase in Veh-treated, but not G1-treated, rats in response to ovariectomy. A-192621 increased blood pressure in NS-fed Veh and G1-treated rats. G1 improved the circadian blood pressure rhythms which were disrupted in A-192621-treated ovariectomized rats. Thus, although systemic GPER1 activation did not protect ovariectomized rats from hypertension and salt sensitivity induced by ETB antagonism, it maintained the circadian blood pressure rhythms. Functional ETB is required to elicit the antihypertensive actions of GPER1. Additional studies are needed to improve our understanding of the interaction between G protein-coupled receptors in regulating circadian blood pressure rhythm.

Endothelial histone deacetylase 1 activity impairs kidney microvascular NO signaling in rats fed a high-salt diet.

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.

Current perspective on circadian function of the kidney.

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.