Despite major advances in understanding the pathophysiology of hypertension and availability of effective and safe antihypertensive drugs, suboptimal blood pressure (BP) control is still the most important risk factor for cardiovascular mortality and is globally responsible for more than 7 million deaths annually. Short-term and long-term BP regulation involve the integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems. Clinical and experimental observations strongly support a central role for the kidneys in the long-term regulation of BP, and abnormal renal-pressure natriuresis is present in all forms of chronic hypertension. Impaired renal-pressure natriuresis and chronic hypertension can be caused by intrarenal or extrarenal factors that reduce glomerular filtration rate or increase renal tubular reabsorption of salt and water; these factors include excessive activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, increased formation of reactive oxygen species, endothelin, and inflammatory cytokines, or decreased synthesis of nitric oxide and various natriuretic factors. In human primary (essential) hypertension, the precise causes of impaired renal function are not completely understood, although excessive weight gain and dietary factors appear to play a major role since hypertension is rare in nonobese hunter-gathers living in nonindustrialized societies. Recent advances in genetics offer opportunities to discover gene-environment interactions that may also contribute to hypertension, although success thus far has been limited mainly to identification of rare monogenic forms of hypertension.

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ET) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ET and ET receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ET receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ET receptor antagonism may provide a strategy for the prevention of renal complications of SCD.

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Background Increases in interleukin 6 (IL-6) and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) are proposed to be important links between placental ischemia and hypertension in preeclampsia. Methods The purpose of this study was to determine whether IL-6 (5 ng/day), infused into normal pregnant (NP) rats, increased mean arterial pressure (MAP) and AT1-AA. MAP was analyzed in the presence and absence of an angiotensin type 1 receptor (AT1R) antagonist, losartan, L. Results MAP and AT1-AA increased from 102 ± 2 to 118 ± 4 mmHg and 0.7 ± 0.3 NP to 14.1 ± 1.4 chronotropic units with chronic IL-6 infusion. MAP responses to IL-6 were abolished in losartan pretreated rats (85 ± 4 in NP + L vs 85 ± 3 mmHg in IL-6 + L). Conclusion These data indicate that IL-6 stimulates AT1-AA and that activation of the AT1R mediates IL-6 induced hypertension during pregnancy.

The renal tubular epithelial cells produce more endothelin-1 (ET-1) than any other cell type in the body. Moving down the nephron, the amount of ET-1 produced appears fairly consistent until reaching the inner medullary collecting duct, which produces at least 10 times more ET-1 than any other segment. ET-1 inhibits Na+ transport in all parts of the nephron through activation of the ETB receptor, and to a minor extent, the ETA receptor. These effects are most prominent in the collecting duct where ETB receptor activation inhibits activity of the epithelial Na+ channel. Effects in other parts of the nephron include inhibition of Na+/H+ exchange in the proximal tubule and the Na+, K+, 2Cl− co-transporter in the thick ascending limb. In general, the renal epithelial ET-1 system is an integral part of the body’s response to a high salt intake in order to maintain homeostasis and normal blood pressure. Loss of ETB receptor function results in salt sensitive hypertension. The goal of this article is to review the role of renal ET-1 and how it affects Na+ and water transport throughout the nephron.

BACKGROUND AND PURPOSEEndothelin-1 (ET-1) is increased in patients with sickle cell disease and may contribute to the development of sickle cell nephropathy. The current study was designed to determine whether ET-1 acting via the ET A receptor contributes to renal injury in a mouse model of sickle cell disease. EXPERIMENTAL APPROACHAdult, humanized HbSS (homozygous for sickle Hb) mice had increased ET-1 mRNA expression in both the cortex and the glomeruli compared with mice heterozygous for sickle and Hb A (HbAS controls). In the renal cortex, ET A receptor mRNA expression was also elevated in HbSS (sickle) mice although ET B receptor mRNA expression was unchanged. Ligand binding assays confirmed that sickle mice had increased ET A receptors in the renal vascular tissue when compared with control mice. KEY RESULTSIn response to PKC stimulation, reactive oxygen species production by isolated glomeruli from HbSS sickle mice was increased compared with that from HbSA controls, an effect that was prevented by 1 week in vivo treatment with the selective ET A antagonist, ABT-627. Protein and nephrin excretion were both elevated in sickle mice, effects that were also significantly attenuated by ABT-627. Finally, ET A receptor antagonism caused a significant reduction in mRNA expression of NADPH oxidase subunits, which may contribute to nephropathy in sickle cell disease. CONCLUSIONS AND IMPLICATIONSThese data support a novel role for ET-1 in the progression of sickle nephropathy, specifically via the ET A receptor, and suggest a potential role for ET A receptor antagonism in a treatment strategy. AbbreviationsET-1, endothelin-1; HbAS, heterozygous for sickle and Hb A; HbSS, homozygous for sickle Hb; ROS, reactive oxygen species; SAD, HbS Antillies and D-Punjab; SCD, sickle cell disease; SCN, sickle cell nephropathy BJP British Journal of Pharmacology

Objective To determine the effect of an endothelin type A receptor antagonist (ETA) on uterine artery resistive index (UARI) and mean arterial pressure (MAP) in a placental ischemia rat model of pre-eclampsia produced by Reductions in Uterine Perfusion Pressure (RUPP). Study Design UARI was assessed by Doppler velocimetry in the RUPP and normal pregnant controls (NP) on gestation days (GD) 12, 15 and 18. UARI was also determined on GD 18 in NP and RUPP pregnant dams after pretreatment with ETA. MAP was recorded on GD 19. Results The RUPP group had a higher MAP and UARI on GD 15 and 18 than the NP group. Pretreatment with ETA attenuated both the MAP and GD 18 UARI in the RUPP group without affecting these parameters in the NP group. Conclusion The improvement in UARI could be one potential mechanism for the reduction in MAP in response to ETA in pregnant dams with ischemic placentas.

Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor Bmal1. A high-salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin type B (ETB) receptors. Furthermore, ETB receptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting duct Bmal1 regulates blood pressure in a sex-dependent manner. We generated a mouse model that lacks Bmal1 expression in the collecting duct, where ETB receptor abundance is highest. Male, but not female, collecting duct Bmal1 knockout (CDBmal1KO) mice had significantly lower 24-h mean arterial pressure (MAP) than flox controls (105 ± 2 vs. 112 ± 3 mmHg for male mice and 106 ± 1 vs. 108 ± 1 mmHg for female mice, by telemetry). After 6 days on a high-salt (4% NaCl) diet, MAP remained significantly lower in male CDBmal1KO mice than in male flox control mice (107 ± 2 vs. 113 ± 1 mmHg), with no significant differences between genotypes in female mice (108 ± 2 vs. 109 ± 1 mmHg). ETB receptor blockade for another 6 days increased MAP similarly in both male and female CDBmal1KO and flox control mice. However, MAP remained lower in male CDBmal1KO mice than in male flox control mice (124 ± 2 vs. 130 ± 2 mmHg). No significant differences were observed between female CDBmal1KO and flox mice during ETB blockade (130 ± 2 vs. 127 ± 2 mmHg). There were no significant genotype differences in amplitude or phase of MAP in either sex. These data suggest that collecting duct Bmal1 has no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice.