Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension.

Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na-Cl cotransporter (NCC).

NADPH oxidase 1 is a novel pharmacological target for the development of an antiplatelet drug without bleeding side effects.

Growing evidence supports a central role of NADPH oxidases (NOXs) in the regulation of platelets, which are circulating cells involved in both hemostasis and thrombosis. Here, the use of Nox1 and Nox1 mice as experimental models of human responses demonstrated a critical role of NOX1 in collagen-dependent platelet activation and pathological arterial thrombosis, as tested in vivo by carotid occlusion assays. In contrast, NOX1 does not affect platelet responses to thrombin and normal hemostasis, as assayed in tail bleeding experiments.

Oxygen and Carbon Dioxide Rhythms Are Circadian Clock Controlled and Differentially Directed by Behavioral Signals.

Daily rhythms in animal physiology are driven by endogenous circadian clocks in part through rest-activity and feeding-fasting cycles. Here, we examined principles that govern daily respiration. We monitored oxygen consumption and carbon dioxide release, as well as tissue oxygenation in freely moving animals to specifically dissect the role of circadian clocks and feeding time on daily respiration.

Angiotensin II-induced hypertension in rats is only transiently accompanied by lower renal oxygenation.

Activation of the renin-angiotensin system may initiate chronic kidney disease. We hypothesised that renal hypoxia is a consequence of hemodynamic changes induced by angiotensin II and occurs prior to development of severe renal damage. Male Sprague-Dawley rats were infused continuously with angiotensin II (350 ng/kg/min) for 8 days.

Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury.

Tissue hypoxia has been proposed as an important event in renal ischemia-reperfusion injury (IRI), particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats.

Cooperative Oxygen Sensing by the Kidney and Carotid Body in Blood Pressure Control.

Oxygen sensing mechanisms are vital for homeostasis and survival. When oxygen levels are too low (hypoxia), blood flow has to be increased, metabolism reduced, or a combination of both, to counteract tissue damage. These adjustments are regulated by local, humoral, or neural reflex mechanisms.

Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.

Key Points: Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation.

Rhythmic Oxygen Levels Reset Circadian Clocks through HIF1α.

The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks.

Hypertension: a problem of organ blood flow supply-demand mismatch.

This review introduces a new hypothesis that sympathetically mediated hypertensive diseases are caused, in the most part, by the activation of visceral afferent systems that are connected to neural circuits generating sympathetic activity. We consider how organ hypoperfusion and blood flow supply-demand mismatch might lead to both sensory hyper-reflexia and aberrant afferent tonicity. We discuss how this may drive sympatho-excitatory-positive feedback and extend across multiple organs initiating, or at least amplifying, sympathetic hyperactivity.

Prolonged and Continuous Measurement of Kidney Oxygenation in Conscious Rats.

A relative deficiency in kidney oxygenation, i.e., renal hypoxia, may contribute to the initiation and progression of acute and chronic kidney disease.

Elevated Urinary Connective Tissue Growth Factor in Diabetic Nephropathy Is Caused by Local Production and Tubular Dysfunction.

Connective tissue growth factor (CTGF; CCN2) plays a role in the development of diabetic nephropathy (DN). Urinary CTGF (uCTGF) is elevated in DN patients and has been proposed as a biomarker for disease progression, but it is unknown which pathophysiological factors contribute to elevated uCTGF. We studied renal handling of CTGF by infusion of recombinant CTGF in diabetic mice.

Perinatal Inhibition of NF-KappaB Has Long-Term Antihypertensive and Renoprotective Effects in Fawn-Hooded Hypertensive Rats.

Background: Inhibition of transcription factor nuclear factor-kappa B (NFκB) is beneficial in various models of hypertension and renal disease. We hypothesized first that NFκB inhibition during renal development ameliorates hereditary hypertensive renal disease and next whether this was mediated via suppression of peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α).

Methods And Results: Prior to the development of renal injury in fawn-hooded hypertensive (FHH) rats, a model of hypertension, glomerular hyperfiltration, and progressive renal injury, NFkB activity, measured by nuclear protein expression of NFkB subunit p65, was enhanced twofold in 2-day-old male and female FHH kidneys as compared to normotensive Wistar-Kyoto (WKY) rats (P < 0.

Maintenance of hypertensive hemodynamics does not depend on ROS in established experimental chronic kidney disease.

While the presence of oxidative stress in chronic kidney disease (CKD) is well established, its relation to hypertensive renal hemodynamics remains unclear. We hypothesized that once CKD is established blood pressure and renal vascular resistance (RVR) no longer depend on reactive oxygen species. CKD was induced by bilateral ablation of 2/3 of each kidney.

Stabilization of hypoxia inducible factor-1α ameliorates acute renal neurogenic hypertension.

Objectives: Renal neurogenic hypertension (RNH) contributes to cardiovascular morbidity. Renal hypoxia may cause RNH and vice versa, leading to a vicious circle. Hypoxia adaptation is conferred through hypoxia-inducible factors (HIFs).

Telemetry-based oxygen sensor for continuous monitoring of kidney oxygenation in conscious rats.

The precise roles of hypoxia in the initiation and progression of kidney disease remain unresolved. A major technical limitation has been the absence of methods allowing long-term measurement of kidney tissue oxygen tension (Po₂) in unrestrained animals. We developed a telemetric method for the measurement of kidney tissue Po₂ in unrestrained rats, using carbon paste electrodes (CPEs).

Effect of GFR on plasma N-terminal connective tissue growth factor (CTGF) concentrations.

Background: Connective tissue growth factor (CTGF) has a key role in the pathogenesis of renal and cardiac fibrosis. Its amino-terminal fragment (N-CTGF), the predominant form of CTGF detected in plasma, has a molecular weight in the middle molecular range (18 kDa). However, it is unknown whether N-CTGF is a uremic retention solute that accumulates in chronic kidney disease (CKD) due to decreased renal clearance and whether it can be removed by hemodiafiltration.

Perinatal exogenous nitric oxide in fawn-hooded hypertensive rats reduces renal ribosomal biogenesis in early life.

Nitric oxide (NO) is known to depress ribosome biogenesis in vitro. In this study we analyzed the influence of exogenous NO on ribosome biogenesis in vivo using a proven antihypertensive model of perinatal NO administration in genetically hypertensive rats. Fawn-hooded hypertensive rat (FHH) dams were supplied with the NO-donor molsidomine in drinking water from 2 weeks before to 4 weeks after birth, and the kidneys were subsequently collected from 2 day, 2 week, and 9 to 10-month-old adult offspring.

Salt sensitivity of blood pressure: developmental and sex-related effects.

Epidemiologic studies have shown convincingly that drastically reducing salt intake in the community is accompanied by blood pressure reductions that are comparable to those achieved by antihypertensive medication. Moreover, many subjects with hypertension are salt sensitive. This implies that, in these subjects, blood pressure is more responsive to changes in salt intake than in subjects with normal blood pressure.

Perinatal inhibition of NF-kappaB has long-term antihypertensive effects in spontaneously hypertensive rats.

Background: Excessive reactive oxygen species (ROS) activate the inflammatory transcription factor nuclear factor-kappa B (NF-κB). ROS-induced inflammation appears to be an early event in the development of hypertension in different models. In the spontaneously hypertensive rat (SHR) we investigated whether perinatal inhibition of NF-κB persistently decreases blood pressure.

Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats.

We hypothesized that perinatal inhibition of soluble epoxide hydrolase (SEH), which metabolizes epoxyeicosatrienoic acids in the arachidonic acid (AA) cascade, with an orally active SEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), would persistently reduce blood pressure (BP) in adult SHR despite discontinuation of AUDA at 4 wk of age. Renal cytoplasmic epoxide hydrolase-2 (Ephx2) gene expression was enhanced in SHR vs. WKY from 2 days to 24 wk.

Perinatal micronutrient supplements ameliorate hypertension and proteinuria in adult fawn-hooded hypertensive rats.

Background: In fawn-hooded hypertensive (FHH) rats, a model of hypertension, impaired preglomerular resistance, hyperfiltration, and progressive renal injury, we recently observed that supporting perinatal nitric oxide (NO) availability with the NO donor molsidomine persistently reduced blood pressure (BP) and ameliorated renal injury in male and female offspring. However, beneficial effects of perinatal molsidomine treatment were more pronounced in female than in male FHH rats.

Methods: To evaluate whether such protective effects could also be achieved with micronutrients, and whether the gender-dependent differences could be confirmed, we tested perinatal exposure to the micronutrients L-arginine, taurine, vitamin C, and vitamin E (ATCE) in FHH rats.

Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion.

Connective tissue growth factor (CTGF) plays a key role in renal fibrosis. Urinary CTGF is elevated in various renal diseases and may have biomarker potential. However, it is unknown which processes contribute to elevated urinary CTGF levels.

Blood pressure follows the kidney: Perinatal influences on hereditary hypertension.

Epidemiological and experimental data strongly suggest that cardiovascular diseases can originate from an aberrant environment during fetal development, a phenomenon referred to as perinatal programming. This review will focus on the role of the kidneys in determining blood pressure, and how (re)programming the renal development can persistently ameliorate hereditary hypertension. By combining physiologic and genomic studies we have discovered some candidate pathways suited for (re)programming the development of hypertension.