Gonadal steroids, salt-sensitivity and renal function

PURPOSE OF REVIEW: The aim of this article is to discuss the impact of male and female sex hormones on renal function and to develop the concept that salt-sensitivity of renal function behaves independently of the systemic blood pressure response to salt and may contribute to renal sex-specific differences. RECENT FINDINGS: Men exhibit a more rapid age-related decline in renal function than women and some renal diseases are clearly sex dependent. Recent studies have shown that gonadal steroids have an important influence on sodium handling and renal hemodynamics that may offer a key for understanding the sexual dimorphism of the renal function. It has been found that androgens increase proximal sodium reabsorption and intraglomerular pressure by modulating afferent and efferent arteriolar tonus via angiotensin II, endothelin and oxidative stress. In contrast, female sex hormones lead to a renal vasodilation and decrease filtration fraction. SUMMARY: Some newly discovered mechanisms triggering the salt-sensitivity of the renal function and the interaction between gonadal steroids and components of the renin cascade may play an important role in the dimorphism of renal response to salt.     

Nitric oxide, angiotensin II, and hypertension

Although initially adaptive, the changes that accompany hypertension, namely, cell growth, endothelial dysfunction, and extracellular matrix deposition, eventually can become maladaptive and lead to end-organ disease such as heart failure, coronary artery disease, and renal failure. A functional imbalance between angiotensin II (Ang II) and nitric oxide (NO) plays an important pathogenetic role in hypertensive end-organ injury. NO, an endogenous vasodilator, inhibitor of vascular smooth muscle and mesangial cell growth, and natriuretic agent, is synthesized in the endothelium by a constitutive NO synthase. NO antagonizes the effects of Ang II on vascular tone, cell growth, and renal sodium excretion, and also down-regulates the synthesis of angiotensin-converting enzyme (ACE) and Ang II type 1 receptors. On the other hand, Ang II decreases NO bioavailability by promoting oxidative stress. A better understanding of the pathophysiologic mechanisms involved in hypertensive end-organ damage may aid in identifying markers of cardiovascular susceptibility to injury and in developing therapeutic interventions. We propose that those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents such as Ang II and NO within the vessel wall would be more effective in preventing or arresting end-organ disease.     

Nitric oxide, salt sensitivity, and cardiorenal injury in hypertension

A connection between salt sensitivity and hypertension seems certain, but a number of issues remain unresolved, e.g., the mechanisms involved in salt sensitivity, its role in pathogenesis and/or maintenance of hypertension, and its ability to predict cardiorenal risk. The role of nitric oxide (NO) has been studied extensively. Evidence shows that NO, along with the vasoactive substances angiotensin II and endothelin-1, is important in modulating vascular tone. In addition, imbalances among these substances may participate in the abnormal cardiovascular and renal remodeling that occurs in hypertension. What causes such imbalances remains unclear. Animal studies show that in salt-sensitive subjects, the activity of NO synthase (NOS) fails to upregulate in response to increases in blood pressure, but that such activity upregulates rapidly in similar circumstances in non-salt-sensitive subjects. Human studies of essential hypertensives have shown an association between salt sensitivity and a number of conditions, including impaired endothelium-dependent relaxation mediated by NO, insulin resistance, microalbuminuria, and ventricular hypertrophy and cardiovascular events. These findings have intriguing implications in regard to whether, in hypertension, salt sensitivity might be a marker of increased cardiovascular and renal risk that is linked to abnormalities in the bioactivity of NO.     

The WNK kinase network regulating sodium, potassium, and blood pressure

The relationship between renal salt handling and hypertension is intertwined historically. The discovery of WNK kinases (With No lysine = K) now offers new insight to this relationship because WNKs are a crucial molecular pathway connecting hormones such as angiotensin II and aldosterone to renal sodium and potassium transport. To fulfill this task, the WNKs also interact with other important kinases, including serum and glucocorticoid-regulated kinase 1, STE20/SPS1-related, proline alanine-rich kinase, and oxidative stress responsive protein type 1. Collectively, this kinase network regulates the activity of the major sodium and potassium transporters in the distal nephron, including thiazide-sensitive Na-Cl cotransporters and ROMK channels. Here we show how the WNKs modulate ion transport through two distinct regulatory pathways, trafficking and phosphorylation, and discuss the physiologic and clinical relevance of the WNKs in the kidney. This ranges from rare mutations in WNKs causing familial hyperkalemic hypertension to acquired forms of hypertension caused by salt sensitivity or diabetes mellitus. Although many questions remain unanswered, the WNKs hold promise for unraveling the link between salt and hypertension, potentially leading to more effective interventions to prevent cardiorenal damage.     

Renal mechanisms of angiotensin II-induced hypertension

The kidneys play a central role in the long-term control of arterial pressure by regulating sodium balance and extracellular fluid volume. The renin-angiotensin system is important in the regulation of the arterial pressure through its chronic effects on the pressure natriuresis relationship. Under physiologic conditions, angiotensin II (Ang II) is important in causing the long-term relationship between arterial pressure and sodium excretion to be very steep, so that minimal changes in arterial pressure are necessary to maintain sodium balance in response to variations in sodium intake. An inability to suppress Ang II formation in response to increases in sodium intake can lead to salt-sensitive hypertension. Excess formation of Ang II, such as in renovascular hypertension, causes the pressure natriuresis relationship to be shifted to higher arterial pressures so that higher arterial pressures are necessary to maintain sodium balance. Ang II decreases pressure natriuresis by enhancing tubular reabsorption and/or reducing glomerular filtration. Because Ang II does not decrease glomerular filtration in most circumstances, the sodium retaining actions of Ang II are usually caused by increased tubular reabsorption. However, there are a number of pathophysiologic conditions where Ang II interacts with various local autocrine and paracrine factors (such as nitric oxide [NO], eicosanoids, adenosine, and superoxide) to influence glomerular filtration rate. Ang II enhances tubular reabsorption either indirectly, through aldosterone stimulation, via alterations in renal hemodynamics (physical factors or medullary blood flow), or by directly enhancing tubular sodium transport. Converting enzyme inhibitors or Ang II receptor antagonists improve pressure natriuresis and are very effective in the treatment of various forms of hypertension associated with normal or enhanced activity of the renin-angiotensin system.     

Renal segmental tubular response to salt during the normal menstrual cycle

BACKGROUND: It has been suggested that women gain weight and develop peripheral edema during the luteal phase of the menstrual cycle because they tend to retain sodium and water. However, there is actually no clear evidence for physiological, cyclic variations in renal sodium handling during the menstrual cycle. We prospectively assessed the changes in segmental renal sodium handling occurring during the menstrual cycle in response to changes in salt intake. METHODS: Thirty-five normotensive women were enrolled. Seventeen women were randomized and studied in the follicular and 18 in the luteal phases of their menstrual cycle. All women were assigned at random to receive a low (40 mmol/day) or a high (250 mmol/day) sodium diet for seven days on two consecutive menstrual cycles. Renal sodium handling and hemodynamics were measured at the end of each diet period. RESULTS: The changes in sodium intake induced comparable variations in sodium excretion in both phases of the menstrual cycle. In the follicular phase, the increase in salt intake was associated with no change in renal hemodynamics, an increased fractional excretion of lithium (FELi) and a decreased fractional distal reabsorption of sodium (FDRNa), suggesting that sodium reabsorption is reduced both in the proximal and the distal tubules. In contrast, in the luteal phase, the renal response to salt was characterized by a significant renal vasodilation and a marked salt escape from the distal nephron, compared to the women investigated in the follicular phase (P < 0.01). Sodium reabsorption by the proximal nephron was not reduced as indicated by the unchanged FELi. CONCLUSIONS: These results show that the segmental renal handling of sodium differs markedly in the two phases of the menstrual cycle. They suggest that the female hormones modulate the renal handling of sodium at the proximal and distal segments of the nephron in young normotensive women.     

The systemic and renal response to NO inhibition is not modified by angiotensin-II-receptor blockade in healthy humans.

BACKGROUND: The role of angiotensin II (Ang II) in the systemic and renal responses to acute nitric oxide (NO) synthesis inhibition has not been studied in detail in healthy humans. The purpose of the present study was to investigate the effects of Ang II receptor blockade on the systemic and renal response to acute treat ment with Ng-monomethyl-L-arginine (L-NMMA) in healthy subjects. METHODS: Mean arterial blood pressure (MAP), renal plasma flow (RPF), glomerular filtration rate (GFR), sodium excretion (UNa*V), and plasma levels of renin, Ang II, ANP, BNP, and cGMP were assessed in 15 healthy sodium replete humans before and after acute L-NMMA treatment (3 mg/kg) on two occasions, i.e. after pretreatment with the Ang II type 1 receptor (AT-1) antagonist candesartan cilexetil (CAND; 8 mg) or placebo in a double blind, randomized fashion. Renal haemodynamics were measured during water diuresis using renal clearances of [125I]hippuran and [51Cr]EDTA. Plasma hormones were measured by radioimmunoassays. RESULTS: On both study days L-NMMA treatment induced a significant increase in MAP and a significant decrease in GFR, RPF, and UNa*V. These effects of L-NMMA were not affected significantly by pretreatment with CAND. The effects of L-NMMA on hormones were roughly similar on both occasions with a drop in P-cGMP and U-cGMP. However, a fall in renin was observed only during CAND pretreatment. CONCLUSIONS: We conclude that Ang II is not a major mediator of acute vasoconstriction and sodium retention during acute lowering of NO activity in healthy man.     

Hypertension and kidney disease

The relationship between chronic kidney disease and hypertension remains enigmatic and a matter of considerable clinical and academic interest, with evidence suggesting that hypertension is both a cause and a consequence of kidney disease. The kidney has a pivotal role in setting the blood pressure in any individual, and this is likely to be related to that individual's sensitivity to salt. The relationship between low birth weight and subsequent hypertension and kidney disease may be predicated on changes in post glomerular phenomena, including sodium transport, although there are differences observed between white and black populations, there being no such clear relationship demonstrable in the latter. Differences in vascular structure may account for some of this variation. There is , by way of example a considerable difference in the risk of death from cardiovascular disease between blacks and Caucasoid populations with renal disease, the former being at greater risk. International moves are now afoot to reduce dietary salt intake. Successful efforts to reduce blood pressure by these or by pharmacological means are likely to reduce death rates, although precise blood pressure targets remain an elusive concept. The possible role of non muscular heavy chain type II isoform A protein which is associated with non diabetic chronic kidney disease in subjects of African ancestry remains to be determined.     

Genetic variation in the epithelial sodium channel: a risk factor for hypertension in people of African origin

High blood pressure occurs commonly in individuals of African origin, leading to an increased risk of cardiovascular and end-stage renal disease (ESRD). Black individuals frequently have low plasma renin activity, and their blood pressure responds well to salt reduction, suggesting that abnormalities in renal sodium handling may be important in the etiology of hypertension in this population. The epithelial sodium channel (ENaC) has a central role in sodium transport across membranes, and in the kidney it contributes to the regulation of blood pressure via changes in sodium balance and blood volume. Rare monogenetic disorders have been described in association with hypertension, such as Liddle's syndrome. In addition, other ENaC polymorphisms have also been described, some of which are more common in black individuals. The T594M polymorphism of ENaC occurs exclusively in black individuals and is associated with hypertension in a black South London population. There is preliminary evidence that amiloride is effective as monotherapy in hypertensives with the T594M polymorphism, and a further study is underway to determine whether this is indeed a safe and specific treatment. If so, then amiloride may provide an important new strategy for blood pressure control in affected black hypertensives.     

Uric acid and the state of the intrarenal renin-angiotensin system in humans

BACKGROUND: Experimental hyperuricemia is marked by an activated intrarenal renin-angiotensin system (RAS). The renal vascular response to exogenous angiotensin II (Ang II) provides an indirect measure of intrarenal RAS activity. We tested the hypothesis that the serum uric acid concentration predicts the renal vascular response to Ang II. METHODS: A total of 249 subjects in high sodium balance had the renal plasma flow (RPF) response to Ang II measured. Para-aminohippuric acid (PAH) clearance was used to estimate RPF. Multivariable regression analysis determined if the serum uric acid concentration independently predicts the RPF response to Ang II. Variables considered included age, gender, race, body mass index (BMI), hypertension status, blood pressure, basal RPF, creatinine clearance, serum insulin, serum glucose, serum high-density lipoprotein (HDL), serum triglycerides, and plasma renin activity (PRA). RESULTS: Uric acid concentration negatively correlated with the RPF response to Ang II (r=-0.37, P < 0.001). In univariate analysis, age, BMI, hypertension, triglycerides, and blood pressure were negatively associated, and basal RPF, HDL, and female gender were positively associated with the RPF response to Ang II. In multivariable analysis, serum uric acid concentration independently predicted the RPF response to Ang II (beta=-5.3, P < 0.001). CONCLUSION: Serum uric acid independently predicted blunted renal vascular responsiveness to Ang II, consistent with results from experimental hyperuricemia showing an activated intrarenal RAS. This could be due to a direct effect of uric acid or reflect a more fundamental renal process. These data may have relevance to the association of uric acid with risk for hypertension and nephropathy.     

Association of renal injury with nitric oxide deficiency in aged SHR: prevention by hypertension control with AT1 blockade

BACKGROUND: Aged spontaneously hypertensive rats (SHR) develop end-stage renal disease resembling that of uncontrolled essential hypertension in humans. Nitric oxide (NO) and angiotensin II (Ang II) play an important role in the regulation of blood pressure and the growth of vascular smooth muscle and renal mesangial cells. The relationship between renal NO system, Ang II activity and renal injury in aged SHR is not fully understood. METHODS: The 8-week-old SHR were randomized into losartan-treated (30 mg/kg/day for 55 weeks) and vehicle treated groups. The age-matched Wistar-Kyoto rats (WKY) served as controls. Renal histology and tissue expressions of endothelial and inducible NO synthases (eNOS and iNOS) and nitrotyrosine were examined at 63-weeks of age. RESULTS: Compared to the WKY group, untreated SHR showed severe hypertension, proteinuria, renal insufficiency, a twofold decrease in renal tissue eNOS and iNOS expressions and massive nitrotyrosine accumulation. This was associated with severe glomerulosclerosis, tubular atrophy and interstitial fibrosis. Losartan therapy normalized blood pressure, prevented proteinuria and renal insufficiency, abrogated the fall in renal eNOS and iNOS protein contents, mitigated renal nitrotyrosine accumulation, and prevented the histological abnormalities found in the untreated SHR. CONCLUSIONS: Aged SHR exhibit severe renal lesions with acquired NO deficiency that are prevented by hypertension control with AT1 blockade. These findings point to the possible role of NO deficiency in the pathogenesis of renal lesions in aged SHR.     

Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal angiotensin II concentrations.

BACKGROUND: Chronic nitric oxide synthase (NOS) inhibition results in hypertension, proteinuria, and renal morphological changes. Continuous angiotensin II (Ang II) blockade prevents these effects, suggesting an essential role of Ang II. However, it is not known whether renal Ang II concentrations are primarily increased or whether the scarcity of NO allows normal concentrations of Ang II to cause these detrimental effects. Therefore, we measured renal Ang II concentrations before and during the development of renal damage. METHODS: Group 1 served as controls. Groups 2 through 5 received the NOS inhibitor Nomega-nitro-L-arginine (L-NNA; 40 mg/kg/day) for 4, 7, 14, and 21 days, respectively. Systolic blood pressure (SBP), proteinuria, glomerular filtration rate (GFR), and renal and blood Ang II were measured. In a separate experiment, rats were treated with L-NNA + the Ang II AT1 receptor blocker losartan to determine the functional effects of endogenous Ang II during chronic NOS inhibition. RESULTS: L-NNA treatment resulted in an increase in SBP from day 4 (161 +/- 4 vs. 135 +/- 4 mm Hg in control, P < 0.05) to day 21 (230 +/- 9 mm Hg). GFR was decreased from day 4 (1.9 +/- 0.2 vs. 2.5 +/- 0.2 ml/min in control, P < 0.05) to day 21 (1.2 +/- 0.2 ml/min). Proteinuria was increased from day 14 (85 +/- 14 vs. 6 +/- 1 mg/day in control, P < 0.05) to day 21 (226 +/- 30 mg/day). L-NNA treatment during four days resulted in a significant decrease in renal Ang II (183 +/- 32 vs. 454 +/- 40 fmol/g in control, P < 0.05). On day 7, 14, and 21, renal Ang II was not significantly different from the control. Blood Ang II was not significantly different from the control on days 4, 7, and 14 but was significantly increased after 21 days of L-NNA treatment (215 +/- 35 vs. 78 +/- 13 fmol/ml in control, P < 0.05). Ang II type-1 (AT1) receptor blockade prevented the severe renal injury and hypertension induced by chronic NOS inhibition. CONCLUSIONS: Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal Ang II concentrations. This suggests that the detrimental effects of endogenous Ang II are increased during chronic NOS inhibition. Thus, when NO levels are low, normal Ang II concentrations can cause renal injury and hypertension.     

Renal hemodynamic and tubular responses to salt in women using oral contraceptives

BACKGROUND: The use of oral contraceptives is associated with an increased risk of developing hypertension but the mechanisms of this hypertensive effect are not completely defined. The purpose of the present study was to assess prospectively the systemic and renal hemodynamic and tubular responses to salt in women taking oral contraceptives. METHODS: Twenty seven young healthy normotensive women taking oral contraceptives containing monophasic combination of 30 microg ethynilestradiol and 150 microg desogestrel for>6 months were enrolled. All women were assigned at random to receive a low (40 mmol/day) or a high (250 mmol/day) sodium diet for 1 week on two consecutive menstrual cycles during the active oral contraceptive phase. At the end of each diet period, 24-hour ambulatory blood pressure, renal hemodynamics, sodium handling, and hormonal profile were measured. RESULTS: The blood pressure response to salt on oral contraceptives was characterized by a salt-resistant pattern with a normal circadian rhythm. Salt loading results in an increase in glomerular filtration rate (GFR) (P < 0.05 vs. low salt), with no change in the renal plasma flow, thus leading to an increase in the filtration fraction (P < 0.05). At the tubular level, women on oral contraceptives responded to a low salt intake with a marked increased in proximal sodium conservation (P < 0.01 vs. high salt) and with an almost complete reabsorption of sodium reaching the distal tubule. After sodium loading, both the proximal and the distal reabsorption of sodium decreased significantly (P < 0.01). CONCLUSION: The use of oral contraceptives is not associated with an increased blood pressure response to salt in young normotensive women. However, oral contraceptives affect the renal hemodynamic response to salt, a high salt intake leading to an increase in GFR and filtration fraction. This effect is possibly mediated by the estrogen-induced activation of the renin-angiotensin system. Oral contraceptives also appear to increase the tubular responsiveness to changes in sodium intake. Taken together, these data point out evidence that synthetic sex steroids have a significant impact on renal function in women. The renal effects of oral contraceptives should be taken into account when managing young women with renal diseases.     

Midkine and the kidney: health and diseases

Midkine (MK; gene name, Mdk), a heparin-binding growth factor, regulates cell growth, cell survival, migration and anti-apoptotic activity in nephrogenesis and development. In the kidney, MK is expressed mainly in proximal tubular epithelial cells and is induced by oxidative stress through the activation of hypoxia-inducible factor-1α. The pathophysiological roles of MK are diverse, ranging from the occurrence of acute kidney injury (AKI) to progression of chronic kidney disease, often accompanied by hypertension, renal ischemia and diabetic nephropathy. In particular, hypertension has indispensable implications for various vascular diseases, including cardiovascular and renal disorders. Mdk(+/+) mice exhibited marked hypertension in renal ablation model compared with Mdk(-/-) mice, eventually leading to more progressive renal failure such as glomerular sclerosis and tubulointerstitial injuries in association with elevated plasma angiotensin (Ang) II levels. MK is also induced in the lung endothelium by oxidative stress and subsequently up-regulated angiotensin-converting enzyme (ACE) in the lung. Ang II is hydrolyzed by ACE to induce further oxidative stress, accelerating MK generation and leading to a vicious cycle of positive feedback on the MK-Ang II pathway. The kidney-lung interaction involving positive feedback between the renin-angiotensin system and MK may in part account for the pathogenesis of hypertension and kidney injury. In addition to this pathway, MK is involved in the pathogenesis of diabetic nephropathy and AKI through the recruitment of the inflammatory cells. Such multidisciplinary findings may open new avenues for targeting therapies for hypertension and various renal diseases, including AKI and diabetic nephropathy.     

Involvement of glomerular renin?angiotensin system (RAS) activation in the development and progression of glomerular injury

Recently, there has been a paradigm shift away from an emphasis on the role of the endocrine (circulating) renin-angiotensin system (RAS) in the regulation of the sodium and extracellular fluid balance, blood pressure, and the pathophysiology of hypertensive organ damage toward a focus on the role of tissue RAS found in many organs, including kidney. A tissue RAS implies that RAS components necessary for the production of angiotensin II (Ang II) reside within the tissue and its production is regulated within the tissue, independent of the circulating RAS. Locally produced Ang II plays a role in many physiological and pathophysiological processes such as hypertension, inflammation, oxidative stress, and tissue fibrosis. Both glomerular and tubular compartments of the kidney have the characteristics of a tissue RAS. The purpose of this article is to review the recent advances in tissue RAS research with a particular focus on the role of the glomerular RAS in the progression of renal disease.     

Nitric oxide and cardiovascular and renal effects

Nitric oxide (NO) has multiple protective effects for regulating the cardiovascular and renal systems. The major functions include endothelium-dependent relaxation, anti-inflammatory effects, as well as antihypertrophic and antithrombotic activities. Many of the activities mediated by NO are systematically antagonized by angiotensin-II (Ang II), a vasconstrictor peptide. Studies described in the review below have demonstrated that the balance between NO and Ang II activities rather than the absolute concentration of each molecule determines their effects on the physiology and pathophysiology of the cardiovascular and renal systems. NO donors have been used for years as therapeutic agents for a range of cardiovascular conditions including angina, myocardial infarction and for the reduction of arterial stiffness. An understanding of the mechanisms underlying the effects of these medications will enable the development of novel therapies to balance the effects of NO in the cardiovascular system.     

Renal expression of constitutive NOS and DDAH: separate effects of salt intake and angiotensin

BACKGROUND: Nitric oxide (NO) is generated from NO synthase (NOS) isoforms. These enzymes can be inhibited by asymmetric dimethylarginine, which is inactivated by N(G)-N(G)-dimethylarginine dimethylaminohydrolase (DDAH). The neuroneal (nNOS) type I and endothelial (eNOS) type III constitutive NOS isoforms are expressed predominantly in the macula densa and microvascular endothelium of the renal cortex, respectively. DDAH is expressed at sites of NOS expression. Since NO may coordinate the renal responses to angiotensin II (Ang II) and changes in salt intake, we tested the hypothesis that salt intake regulates the expression of nNOS, eNOS and DDAH by Ang II acting on type 1 (AT(1)) receptors. METHODS: Groups (N = 6) of rats were adapted to low-salt (LS) or high-salt (HS) intakes for 10 days. Other groups of LS and HS rats received the AT(1) receptor antagonist losartan for six days (to test the effects of salt independent of AT(1) receptors). A further group of HS rats received an infusion of Ang II for six days (to test the effect of Ang II independent of salt intake). RESULTS: Compared with HS rats, there was a significant (P < 0.05) increase in LS rats of nNOS protein in kidney and immunohistochemical expression in the macula densa, and of eNOS protein expression and immunohistochemical expression in the microvascular endothelium, and of DDAH protein expression. Losartan prevented these effects of salt on the expression of eNOS or DDAH, both of which were also increased by Ang II infusions in HS rats. In contrast, losartan did not prevent the effects of salt on nNOS expression, which was unresponsive to Ang II infusion. The generation of NO(2)(-) released by slices of renal cortex, in the presence of saturating concentrations of L-arginine, was increased by LS, compared to HS, independent of losartan and by Ang II during HS. CONCLUSION: The expressions of eNOS in cortical microvascular endothelium and DDAH in kidney are enhanced by Ang II acting on AT(1) receptors. The expression of nNOS in the macula densa is enhanced by salt restriction independent of Ang II or AT(1) receptors.     

Vascular endothelium and nitric oxide in childhood hypertension

Vascular endothelium releases nitric oxide (NO), an important vasodilator that is continuously synthesised by the constitutive enzyme, endothelial nitric oxide synthase (NOS). This maintains a constant vasodilator tone which is diminished in adult hypertension, due to reduced endothelium-dependent vascular relaxation, which is NO dependent. In childhood, however, hypertension is often secondary, and normalisation of blood pressure by removal of cause (e.g. renal artery stenosis, catecholamine-producing tumour) suggests reversibility of endothelial dysfunction, if it is present. Raised plasma levels of endogenous inhibitors have been found, especially in children with secondary hypertension due to renal parenchymal and renovascular disease, and may contribute to hypertension by more than just inhibition of vascular NO release; e.g. by reduction of glomerular filtration rate and promotion of salt and water retention. These inhibitors also modulate renin release, which may be of relevance in cardiovascular physiology, and may also interfere with the anti-platelet properties of NO, increasing the likelihood of vascular thrombotic events. NO inhibitors also promote endothelial activation, with increased expression of adhesion molecules that may form seedlings of atherosclerosis. In chronic renal impairment, accumulation of NO inhibitors may contribute to hypertension. Efficient long-session dialysis helps better interdialysis control of blood pressure in these subjects, independent of salt and water removal, suggesting that removal of such vasoactive agents may be important for efficient blood pressure control. There are a few studies assessing NO generation in hypertensive children via plasma nitrite and nitrate, the NO end products, which suggest normal or increased production as opposed to a reduction, perhaps as a compensatory phenomenon. In the treatment of hypertension, nitroprusside and nitrates exert their actions via NO donation. Excessive production of NO (usually via inducible NOS) or excessive administration (nitrovasodilators) can be cytotoxic and may cause hypotension and shock, as in severe sepsis. NOS inhibitors and NO therefore appear to play a crucial role in aetiology, complications and therapy of childhood hypertension. Received November 24, 1997; received in revised form and accepted April 6, 1998     

Mechanisms of disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity

Hypertension and salt sensitivity of blood pressure are two conditions the etiologies of which are still elusive because of the complex influences of genes, environment, and behavior. Recent understanding of the molecular mechanisms that govern sodium homeostasis is shedding new light on how genes, their protein products, and interacting metabolic pathways contribute to disease. Sodium transport is increased in the proximal tubule and thick ascending limb of Henle of the kidney in human essential hypertension. This Review focuses on the counter-regulation between the dopaminergic and renin-angiotensin systems in the renal proximal tubule, which is the site of about 70% of total renal sodium reabsorption. The inhibitory effect of dopamine is most evident under conditions of moderate sodium excess, whereas the stimulatory effect of angiotensin II is most evident under conditions of sodium deficit. Dopamine and angiotensin II exert their actions via G protein-coupled receptors, which are in turn regulated by G protein-coupled receptor kinases (GRKs). Polymorphisms that lead to aberrant action of GRKs cause a number of conditions, including hypertension and salt sensitivity. Polymorphisms in one particular member of this family-GRK4-have been shown to cause hyperphosphorylation, desensitization and internalization of a member of the dopamine receptor family, the dopamine 1 receptor, while increasing the expression of a key receptor of the renin-angiotensin system, the angiotensin II type 1 receptor. Novel diagnostic and therapeutic approaches for identifying at-risk subjects, followed by selective treatment of hypertension and salt sensitivity, might center on restoring normal receptor function through blocking the effects of GRK4 polymorphisms.     

Role of angiotensin II in glomerular injury.

The components of the renin-angiotensin system (RAS) in progressive renal disease have been extensively investigated, indicating multiple actions beyond hemodynamic and salt/water homeostasis. Studies in various human diseases and in animal models have shown that angiotensin (Ang) I-converting enzyme inhibitors (ACEI) are superior to other antihypertensive agents in protecting the kidney against progressive deterioration, even in conditions without systemic hypertension. These findings suggest that Ang II has nonhemodynamic effects in progressive renal disease. Interactions of the RAS with aldosterone and bradykinin may have impact on both blood pressure and tissue injury. The RAS is now recognized to be linked to induction of plasminogen activator inhibitor-1 (PAI-1) likely via both the type 1 (AT1) and type 4 (AT4) receptors, thus, promoting both thrombosis and fibrosis. A role of angiotensin in the regulation of immune injury and inflammation has also been identified. Polymorphisms of genes relevant to the RAS appear to affect the risk and course of cardiovascular and renal diseases and response to treatment. The beneficial effect on renal fibrosis of inhibiting the RAS likely reflects the central role that angiotensin has in regulating renal function and structure by its multifaceted actions. This article will focus on the role of the RAS in glomerular injury.