Abnormal Renal Sodium Handling Research Articles

Is renal ß-adrenergic-WNK4-NCC pathway important in salt hypertension of Dahl rats?

In 2011 Fujita and coworkers proposed that ß-adrenergic stimulation causes decreased serine/threonine-protein kinase WNK4 transcription leading to the activation of Na-Cl cotransporter (NCC) which participates in salt sensitivity and salt hypertension development in rodents. The aim of our study was to investigate whether the above hypothesis is also valid for salt hypertension of Dahl rats, which are characterized by high sympathetic tone and abnormal renal sodium handling. Male 8-week-old salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats were fed either low-salt diet (LS, 0.4 % NaCl) or high-salt diet (HS, 4 % NaCl) for 6 weeks. Half of the animals on either diet were chronically treated with non-selective ß-blocker propranolol (100 mg/kg/day). At the end of the experiment diuresis and sodium excretion were measured prior and after hydrochlorothiazide injection (HCTZ, 10 mg/kg i.p.). Furthermore, blood pressure (BP), heart rate (HR), sympathetic (pentolinium 5 mg/kg i.v.) and NO-dependent (L-NAME 30 mg/kg i.v.) BP components were determined. Chronic HS diet feeding increased BP through sympathoexcitation in SS/Jr but not in SR/Jr rats. Concomitant propranolol treatment did not lower BP in either experimental group. Under the conditions of low salt intake HCTZ increased diuresis, natriuresis and fractional sodium excretion in SR/Jr but not in SS/Jr rats. HS diet feeding attenuated renal response to HCT in SR/Jr rats, whereas no HCTZ effect was observed in SS/Jr rats fed HS diet. Propranolol treatment did not modify diuresis or natriuresis in any experimental group. In conclusions, our present data do not support the idea on the essential importance of renal ß-adrenergic-WNK4-NCC pathway in pathogenesis and/or maintenance of salt hypertension in Dahl rats.

The exaggerated natriuresis of essential hypertension occurs independently of changes in renal medullary blood flow.

In patients with essential hypertension, abnormal renal sodium handling includes exaggerated natriuresis in response to extracellular volume expansion. We tested the hypothesis that exaggerated natriuresis is associated with increases in medullary and/or cortical renal blood flow. Patients with mild essential hypertension, but no signs of end organ damage, and control subjects were studied after 4days of dietary standardization (<60mmol Na+ day-1 ) preceded in patients by a 14-day drug washout period. On the study day, subjects received a 4-hour intravenous volume expansion with saline (2.1% of body mass). Renal medullary and cortical blood flows were measured by PET scanning using H215 O as tracer; anatomical regions of interest were defined by contrast-enhanced CT scanning. In patients, arterial blood pressure increased during volume expansion (107±2-114±3mmHg, P<0.05) in contrast to the control group (92±2-92±2mmHg). Renal sodium excretion increased more in patients than in controls (+133±31µmolmin-1 vs +61±14µmolmin-1 , respectively, P<0.05) confirming exaggerated natriuresis. During volume expansion, renal medullary blood flow did not change significantly in patients (2.8±0.4-2.5±0.5mL (g tissue)-1 min-1 ) or in controls (3.2±0.3-3.1±0.2mL (g tissue)-1 min-1 ). In control subjects, renal cortical blood flow fell during volume expansion (4.1±0.3-3.7±0.2mL (g tissue)-1 min-1 , P<0.05) in contrast to patients in which deviations remained insignificant. Exaggerated natriuresis, a hallmark of essential hypertension, is not mediated by increases in regional, renal blood flow.

Recent advances in understanding hypertension development in sub-Saharan Africa.

Consistent reports indicate that hypertension is a particularly common finding in black populations. Hypertension occurs at younger ages and is often more severe in terms of blood pressure levels and organ damage than in whites, resulting in a higher incidence of cardiovascular disease and mortality. This review provides an outline of recent advances in the pathophysiological understanding of blood pressure elevation and the consequences thereof in black populations in Africa. This is set against the backdrop of populations undergoing demanding and rapid demographic transition, where infection with the human immunodeficiency virus predominates, and where under and over-nutrition coexist. Collectively, recent findings from Africa illustrate an increased lifetime risk to hypertension from foetal life onwards. From young ages black populations display early endothelial dysfunction, increased vascular tone and reactivity, microvascular structural adaptions as well as increased aortic stiffness resulting in elevated central and brachial blood pressures during the day and night, when compared to whites. Together with knowledge on the contributions of sympathetic activation and abnormal renal sodium handling, these pathophysiological adaptations result in subclinical and clinical organ damage at younger ages. This overall enhanced understanding on the determinants of blood pressure elevation in blacks encourages (a) novel approaches to assess and manage hypertension in Africa better, (b) further scientific discovery to develop more effective prevention and treatment strategies and

Hydrogen sulphide and tempol treatments improve the blood pressure and renal excretory responses in spontaneously hypertensive rats

Oxidative stress and suppressed H2S production lead to increased renal vascular resistance, disturbed glomerular hemodynamics, and abnormal renal sodium and water handling, contribute to the pathogenesis and maintenance of essential hypertension in man and the spontaneously hypertensive rat. This study investigated the impact of H2S and tempol alone and in combination on blood pressure and renal hemodynamics and excretory functions in the SHR. Groups of WKY rats or SHR (n = 6) were treated for 4 weeks either as controls or received NaHS (SHR + NaHS), tempol (SHR + Tempol), or NaHS plus tempol (SHR + NaHS + Tempol). Metabolic studies were performed on days 0, 14, and 28, thereafter animals were anaesthetized to measure renal hemodynamics and plasma oxidative and antioxidant markers. SHR control rats had higher mean arterial blood pressure (140.0 ± 2 vs. 100.0 ± 3 mmHg), lower plasma and urinary H2S, creatinine clearance, urine flow rate and urinary sodium excretion, and oxidative stress compared to WKY (all p < 0.05). Treatment either with NaHS or with tempol alone decreased blood pressure and oxidative stress and improved renal hemodynamic and excretory function compared to untreated SHR. Combined NaHS and tempol therapy in SHRs caused larger decreases in blood pressure (∼20–22% vs. ∼11–15% and ∼10–14%), increases in creatinine clearance, urinary sodium excretion and fractional sodium excretion and up-regulated the antioxidant status compared to each agent alone (all p < 0.05). These findings demonstrated that H2S and tempol together resulted in greater reductions in blood pressure and normalization of kidney function compared with either compound alone.

Dopamine‐mediated inhibition of renal Na+/K+‐ATPase in HK‐2 cells is reduced by ouabain

1. Abnormal renal sodium handling is considered a major contributing factor in hypertension associated with chronic ouabain treatment. However, the molecular mechanisms involved in abnormal renal sodium handling have not been elucidated. Therefore, we investigated whether chronic ouabain treatment perturbs dopamine D(1) receptor function. 2. The expression and phosphorylation levels of the D(1) receptor in cells of the human proximal tubule cell line (HK-2) were determined using western blot analysis and reverse transcription polymerase chain reaction. The activity of the renal sodium/potassium pump (Na(+)/K(+)-ATPase) was measured using a colourimetric assay, and cyclic adenosine monophosphate accumulation was determined by performing a radioimmunoassay. 3. We showed that chronic ouabain treatment decreased the protein and mRNA expression levels of the D(1) receptor and increased the basal phosphorylation of the D(1) receptor in HK-2 cells. We also showed that in the presence of ouabain, HK-2 cells did not reveal the cyclic adenosine monophosphate accumulation and Na(+)/K(+)-ATPase inhibition induced by the D(1) receptor agonist fenoldopam. 4. We hypothesize that the ouabain-induced decrease in renal D(1) receptor function is responsible for the increase in renal sodium reabsorption, which eventually leads to ouabain-induced hypertension.

New role for plasmin in sodium homeostasis

Hypertension and edema are clinical manifestations of the extracellular volume expansion generated by abnormal renal sodium handling. Perturbations in epithelial sodium channel (ENaC) activity disrupt volume homeostasis. ENaC activity can be enhanced by proteases that cleave its long extracellular domains. Recent evidence suggests that this mechanism may be involved in individuals with volume overload and proteinuria. Several observations indicate a link between proteinuria and hypertension, with proteinuria preceding and predicting the onset of incident hypertension in some individuals. Recently, enhanced cleavage of ENaC's extracellular loops was identified in kidney tissue of proteinuric mice. Plasmin, a serine protease known for its role in fibrinolysis, has been implicated as an activator of ENaC in proteinuric states as nephrotic urine activates ENaC expressed in a mouse collecting duct cell line, aprotinin-affinity precipitation of nephrotic urine abolishes its ability to activate ENaC, plasmin is a major component within aprotinin-affinity purified nephrotic urine and is absent in nonproteinuric urine, and plasmin activates ENaC by cleaving the extracellular loop of its gamma subunit. Enhancement of ENaC activity by proteases represents a likely mechanism for extracellular volume overload relevant to some individuals with proteinuria. Proteases not normally found in the urine can enter the urinary space across damaged glomeruli and activate ENaC. Further understanding of this mechanism may guide targeted therapeutics in individuals with proteinuria, edema, and hypertension.

Can nocturnal hypertension predict cardiovascular risk?

Nocturnal hypertension and non-dipping of blood pressure during sleep are distinct entities that often occur together and are regarded as important harbingers of poor cardiovascular prognosis. This review addresses several aspects related to these blood pressure abnormalities including definitions, diagnostic limitations, pathogenesis and associated patient profiles, prognostic significance, and therapeutic strategies. Taken together, persistent nocturnal hypertension and non-dipping blood pressure pattern, perhaps secondary to abnormal renal sodium handling and/or altered nocturnal sympathovagal balance, are strongly associated with deaths, cardiovascular events, and progressive loss of renal function, independent of daytime and 24-hour blood pressure. Several pharmacological and non-pharmacological approaches may restore nocturnal blood pressure and circadian blood pressure rhythm to normal; however, whether this translates to a clinically meaningful reduction in unfavorable cardiovascular and renal consequences remains to be seen.

Pendrin as a regulator of ECF and blood pressure

Abnormal renal sodium handling plays a pivotal role in the pathophysiology of arterial hypertension. Though sodium is present in the diet as a chloride salt, most studies have focused on the renal mechanisms of sodium transport and their regulation, and very few have investigated the impact of chloride. However, strong evidence indicates that chloride may play a very important role in the 'prohypertensive' effects of sodium. Several observations indicate that sodium has to be administered as NaCl and not as NaHCO3 to raise arterial blood pressure. Recently, genetic studies have pointed out the critical role of the most distal parts of the nephron in regulating sodium balance and blood pressure. Interestingly, in those segments, the transport of Na+ and Cl- proceeds separately, through different molecules. Recent evidence has demonstrated that an apical Cl-/HCO3- exchanger called pendrin is an absolute requirement for chloride reabsorption in the collecting system, indicating that chloride absorption is not passive and paracellular but is mediated by the intercalated cells. Importantly, pendrin disruption protects mice against mineralocorticoid-induced hypertension and impairs renal adaptation to a low NaCl diet. Moreover, recent findings suggest several mechanisms by which chloride transport might affect NaCl balance and blood pressure. Pendrin-mediated chloride transport through intercalated cells appears to be an independent and important determinant of renal NaCl handling and therefore might represent a new target for blood pressure control.

Mechanisms of hypertension in the cardiometabolic syndrome

Arterial hypertension is often part of a constellation of anthropometric and metabolic abnormalities that occur simultaneously to a higher degree than would be expected by chance alone, supporting the existence of a discrete disorder, the so-called metabolic syndrome. It is the result of interactions among a large number of interconnected mechanisms, which eventually lead to both an increase in cardiovascular and renal risk, and the development of diabetes. Mechanisms involved in the metabolic syndrome are obesity, insulin resistance, and a constellation of independent factors, which include molecules of hepatic, vascular, and immunologic origin with pro-inflammatory properties. At each of these key points are interactions of demographics, lifestyle, genetic factors, and environmental fetal programming. Superimposing upon these are infections or chronic exposure or both to certain drugs that can also make their contribution. Skeletal muscle and the liver, not adipose tissue, are the two key insulin-response tissues involved in maintaining glucose balance, although abnormal insulin action in the adipocytes also plays a role in development of the syndrome. Factors commonly associated with and partly dependent on obesity, insulin resistance, such as overactivity of the sympathetic, stimulation of the renin-angiotensin-aldosterone systems, abnormal renal sodium handling, endothelial dysfunction, and large vessels' alterations, may play a key role in the blood pressure elevation of the syndrome.

Physiologic regulation of the epithelial sodium channel by phosphatidylinositides

Epithelial sodium channel (ENaC) activity is limiting for sodium reabsorption in the distal nephron. Humans regulate blood pressure by fine-tuning sodium balance through control of ENaC. ENaC dysfunction causes some hypertensive and renal salt wasting diseases. Thus, it is critical to understand the cellular mechanisms controlling ENaC activity. ENaC is sensitive to phosphatidylinositol 4,5-bisphosphate (PIP2), the target of phospholipase C-mediated metabolism, and phosphatidylinositiol 3,4,5-trisphosphate (PIP3), the product of phosphatidylinositide 3-OH kinase (PI3-K). PIP2 is permissive for ENaC gating possibly interacting directly with the channel. Activation of distal nephron P2Y receptors tempers ENaC activity by promoting PIP2 metabolism. This is important because gene deletion of P2Y2 receptors causes hypertension associated with hyperactive ENaC. Aldosterone, the final hormone in a negative-feedback cascade activated by decreases in blood pressure, increases ENaC activity. PIP3 sits at a critical bifurcation in the aldosterone-signaling cascade, increasing ENaC open probability and number. PIP3-effectors mediate increases in ENaC number by suppressing channel retrieval. PIP3 binds ENaC, at a site distinct from that important to PIP2 regulation, to modulate directly open probability. Phosphoinositides play key roles in physiologic control of ENaC and perhaps dysregulation plays a role in disease associated with abnormal renal sodium handling.

The Roles of Abnormal Renal Sodium Handling in Hypertension Associated with Metabolic Syndrome

There is an epidemic of the metabolic syndrome across the world, which is often associated with hypertension and other coronary risk factors. Insulin resistance is thought to play a key role in this condition. Several different mechanisms such as activation of renin-angiotensin system, enhancement of sympathetic nerve system, and hyperinsulinemia may underlie hypertension in metabolic syndrome. Unlike in other tissues, angiotensin II regulates renal proximal tubule transport in a biphasic manner. The molecular mechanism for the angiotensin II-mediated regulation of renal proximal transport has been recently clarified. On the other hand, insulin stimulates sodium transport in several nephron segments including proximal tubules. Recent data have shown that the sodium-retaining effect of insulin is paradoxically preserved in a mouse model of insulin resistance, which may be enhanced by sympathetic nerve activation. In this review, we will focus on the roles of abnormal renal proximal tubule sodium handling in hypertension. Keywords: Renal proximal tubules, angiotensin II, norepinephrine, insulin, IRS

Renal sodium handling in patients with normal pressure glaucoma

Low BP (blood pressure) is a recognized risk factor for some patients with NPG (normal pressure glaucoma). We have shown previously that patients with orthostasis have impaired circadian renal handling of sodium, which may contribute to the low BP. Therefore the aim of the present study was to examine the renal handling of sodium, the circadian variations in BP and the neurohormonal response to an orthostatic test in a selected subpopulation of 18 patients with NPG with vasospastic and orthostatic symptoms, and in 24 healthy control subjects. The variations in BP and renal tubular sodium handling were evaluated using 24 h ambulatory BP recordings, 24 h urine collections and determination of endogenous lithium clearance as a marker of proximal sodium reabsorption. The neurohormonal and BP responses to changes in posture were also determined in a 30 min orthostatic test. This selected group of patients with NPG had lower 24 h ambulatory BPs (P<0.001), and a more pronounced fall in BP when assuming an upright position (P<0.001) compared with controls. FE(Li) (fractional excretion of lithium) was higher in patients with NPG than controls during the day (36.6+/-21.8 compared with 20.4+/-8.7% respectively; P<0.01; values are means+/-S.D.) as well as during the night (38.8+/-41.9 compared with 19.7+/-10.8% respectively; P<0.02), suggesting a reduced reabsorption of sodium in the proximal tubule. This was compensated for by an increased distal reabsorption of sodium in patients with NPG (P<0.01). These data demonstrate that patients with vasospastic NPG have a high excretion of lithium, suggesting reduced sodium reabsorption in the proximal tubule, in spite of a low BP. The abnormal renal sodium handling might contribute to the maintenance of arterial hypotension and progression of the optic nerve damage in these patients.

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

Hypertension-Linked Mutation in the Adducin α-Subunit Leads to Higher AP2-μ2 Phosphorylation and Impaired Na + ,K + -ATPase Trafficking in Response to GPCR Signals and Intracellular Sodium

Alpha-adducin polymorphism in humans is associated with abnormal renal sodium handling and high blood pressure. The mechanisms by which mutations in adducin affect the renal set point for sodium excretion are not known. Decreases in Na+,K+-ATPase activity attributable to endocytosis of active units in renal tubule cells by dopamine regulates sodium excretion during high-salt diet. Milan rats carrying the hypertensive adducin phenotype have a higher renal tubule Na+,K+-ATPase activity, and their Na+,K+-ATPase molecules do not undergo endocytosis in response to dopamine as do those of the normotensive strain. Dopamine fails to promote the interaction between adaptins and the Na+,K+-ATPase because of adaptin-mu2 subunit hyperphosphorylation. Expression of the hypertensive rat or human variant of adducin into normal renal epithelial cells recreates the hypertensive phenotype with higher Na+,K+-ATPase activity, mu2-subunit hyperphosphorylation, and impaired Na+,K+-ATPase endocytosis. Thus, increased renal Na+,K+-ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na+,K+-ATPase endocytosis in response to natriuretic signals.

The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis

Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 age- and sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture– induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensin-aldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture – induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture. (H EPATOLOGY 2002;35:1449-1458.)

The mechanism of improved sodium homeostasis of low-dose losartan in pre-ascitic cirrhosis

Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 ageand sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture– induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensinaldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture – induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture. (HEPATOLOGY 2002; 35:1449-1458.)

Obesity and hypertension

Substantial evidence from epidemiological data supports a link between obesity and hypertension. However, the relationship between the two disorders is not straightforward and most likely represents an interaction of demographic, genetic, hormonal, renal, and hemodynamic factors. Age, race, and sex also modulate the strength of the association between obesity and hypertension. Hyperinsulinemia, which is characteristic of obesity, can contribute to the probability of developing hypertension by activating the sympathetic nervous system (SNS) and by causing sodium retention. The pressor effect of insulin in obesity may be further enhanced by the observation that its vasodilator action can be blunted in obese subjects. Preliminary data have shown that leptin, whose levels are increased in most obese individuals, can contribute to hypertension in obesity through its effects on insulin, SNS, and sodium excretion. The kidney may also have a role in the pathophysiology of hypertension in obesity. Abnormal renal sodium handling coupled with structural changes in the kidney of an obese patient can raise blood pressure. In addition, obesity is associated with distinct cardiovascular hemodynamic alterations and development of eccentric myocardial hypertrophy. Most of these obesity-associated abnormalities, as well as hypertension itself, can be reversed by weight loss. Furthermore, weight loss can prevent, or at least delay, the development of hypertension in patients with high-normal blood pressure. Weight reduction should be the first-line treatment in every obese hypertensive patient. However, the majority of patients will need pharmacologic intervention in conjunction with weight loss. Selection of antihypertensive agents in the overweight patient should take into account the mechanisms leading to hypertension and the metabolic abnormalities that characterize the obese patient. Copyright © 1999 by W.B. Saunders Company Progress in Cardiovascular Diseases, Vol. 42, No. 1 (July/August), 1999: pp 39-58

Current and birth weights exert independent influences on nocturnal pressure-natriuresis relationships in normotensive children.

The objective was to study the impact of birth weight on the relationship between ambulatory blood pressure and urinary sodium excretion in children and adolescents. The study included 134 healthy children (61 boys), all Caucasians, who were born at term after a normotensive pregnancy. For each subject, a 24-hour ambulatory blood pressure monitoring and a complete urine collection were simultaneously performed according to the protocols designed. Average ambulatory blood pressure (BP) and the urinary excretion rates for sodium, potassium, and creatinine were calculated separately for 24-hour, awake, and sleep periods defined by a mini-diary. The excretion rate of sodium during sleep time was positively correlated with ambulatory systolic BP; such a positive relationship was not found for waking hours. Consequently, the impact of birth weight on the relationship between blood pressure and the urinary sodium excretion rate was analyzed during sleeping hours. Stepwise multiple regression analysis shows that although current weight was the strongest predictor for the sodium excretion rate during sleep (P<.001), there was also an independent significant direct relationship for birth weight (P<.04) after controlling for age, sex, and the average of systolic BP during sleep. Adjusted for current weight, a significant difference in the regression slopes relating urinary sodium excretion rate and systolic BP during sleep exists between children in the lowest (<3.100 kg) and the highest tertiles (>3.500 kg) of birth weight (P<.02). Differences in sodium excretion rates, adjusted for current weight, between the two extreme tertiles of birth weight became significant at the highest systolic BP (P<.04). The children who had the lowest birth weight tended to excrete less sodium during sleep. The results of the present study show a blunted pressure natriuresis curve in children and adolescents with the lowest birth weight. Whether this abnormal renal sodium handling may be present as an initial or as an intermediate mechanism leading to higher BP values must be assessed in additional studies.

Mechanisms of Abnormal Renal Sodium Handling in Obesity Hypertension

Obesity-induced hypertension, like all forms of experimental and human hypertension studied thus far, is associated with renal dysfunction characterized by the resetting of pressure natriuresis. In obese subjects, this resetting is primarily a result of increased renal tubular reabsorption as glomerular filtration rate and renal blood flow are markedly elevated. Obesity activates the sympathetic nervous and renin-angiotensin systems, and causes insulin resistance and hyperinsulinemia, all of which have been postulated to increase tubular reabsorption and raise blood pressure. In humans and dogs, chronic hyperinsulinemia, comparable to that found in obesity, does not cause hypertension even in the presence of insulin resistance. Activation of the sympathetic nervous system appears to be important in obesity, as chronic adrenergic blockade or renal denervation greatly ameliorates the hypertension associated with weight gain. Resetting of pressure natriuresis in obesity may also be attributable to altered intrarenal forces caused by histologic changes in the renal medulla that may compress the loops of Henle and vasa recta, increase tubular sodium reabsorption, and activate the renin-angiotensin system. The quantitative importance of these intrarenal changes and their interrelationship with neurohumoral activation in obesity is an important area for further investigation.

Diet, genetics and hypertension.

It is generally accepted that genetics play a significant role in the pathogenesis of hypertension. Since hypertension often follows kidney transplantation, candidate genes have been sought and found in the kidneys of rats and humans. One well-recognized, inherited influence on blood pressure (BP) occurs via abnormal renal sodium handling in vivo. Further, abnormal renal sodium handling is seen in isolated kidneys of genetically hypertensive rats. People who have a relative inability to handle a sodium load properly, and retain it inappropriately, often develop high BP and are referred to as “salt-sensitive”. More than half of patients diagnosed with essential hypertension are salt-sensitive. In contrast to the deleterious effects associated with high sodium intake, many believe that ingestion of more potassium, calcium, and magnesium may influence BP favorably. The beneficial effects of these ions work, at least in part, through an effect on sodium balance, i.e. a diuretic influence. In support of this concept, they lower BP more effectively in salt-sensitive hypertensives. Refined carbohydrates and saturated fats are also associated with salt retention and hypertension. Thus, dietary factors, working directly on their own and/or indirectly via effects on genetic mechanisms, may alter BP favorably or unfavorably.