Medullary and cortical thick ascending limb: similarities and differences.

The thick ascending limb of the loop of Henle (TAL) is the first segment of the distal nephron, extending through the whole outer medulla and cortex, two regions with different composition of the peritubular environment. The TAL plays a critical role in the control of NaCl, water, acid, and divalent cation homeostasis, as illustrated by the consequences of the various monogenic diseases that affect the TAL. It delivers tubular fluid to the distal convoluted tubule and thereby affects the function of the downstream tubular segments. The TAL is commonly considered as a whole. However, many structural and functional differences exist between its medullary and cortical parts. The present review summarizes the available data regarding the similarities and differences between the medullary and cortical parts of the TAL. Both subsegments reabsorb NaCl and have high Na+-K+-ATPase activity and negligible water permeability; however, they express distinct isoforms of the Na+-K+-2Cl- cotransporter at the apical membrane. Ammonia and bicarbonate are mostly reabsorbed in the medullary TAL, whereas Ca2+ and Mg2+ are mostly reabsorbed in the cortical TAL. The peptidic hormone receptors controlling transport in the TAL are not homogeneously expressed along the cortical and medullary TAL. Besides this axial heterogeneity, structural and functional differences are also apparent between species, which underscores the link between properties and role of the TAL under various environments.

Triamterene Enhances the Blood Pressure Lowering Effect of Hydrochlorothiazide in Patients with Hypertension.

BACKGROUND: Triamterene, because of its potassium-sparing properties, is frequently used in combination with hydrochlorothiazide (HCTZ) to treat patients with hypertension. By inhibiting the epithelial sodium channel (ENaC) in the cortical collecting duct, triamterene reduces potassium secretion, thus reducing the risk of hypokalemia. Whether triamterene has an independent effect on blood pressure (BP) has not been well studied. OBJECTIVE: To determine if triamterene provides an effect to further lower BP in patients treated with HCTZ. DESIGN: We conducted an observational study using electronic medical record data from the Indiana Network for Patient Care. Participants were 17,291 patients with the diagnosis of hypertension between 2004 and 2012. MAIN MEASURES: BP was the primary outcome. We compared the BP between patients who were taking HCTZ, with and without triamterene, either alone or in combination with other antihypertensive medications, by using a propensity score analysis. For each medication combination, we estimated the propensity score (i.e., probability) of a patient receiving triamterene using a logistic regression model. Patients with similar propensity scores were stratified into subclasses and BP was compared between those taking triamterene or not within each subclass; the effect of triamterene was then assessed by combining BP differences estimated from all subclasses. KEY RESULTS: The mean systolic BP in the triamterene + HCTZ group was 3.8 mmHg lower than in the HCTZ only group (p < 0.0001); systolic BP was similarly lower for patients taking triamterene with other medication combinations. Systolic BP reduction was consistently observed for different medication combinations. The range of systolic BP reduction was between 1 and 4 mm Hg, depending on the concurrently used medications. CONCLUSIONS: In the present study, triamterene was found to enhance the effect of HCTZ to lower BP. In addition to its potassium-sparing action, triamterene's ability to lower BP should also be considered.

Genetic variation of GPLD1 associates with serum GPI-PLD levels: a preliminary study.

HDL is a heterogeneous mixture of lipoprotein particles varying in composition, size, and function. We and others have described a small (7.0nm), minor (0.1% of total apolipoprotein AI) particle containing apolipoprotein AI, AIV and glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) in humans the function of which is not entirely known. Circulating GPI-PLD levels are regulated by multiple factors including genetics. To determine if genetic variation in GPLD1 affects circulating GPI-PLD levels, we examined the relationship between 32 SNPS upstream, within, and downstream of GPLD1 and circulating GPI-PLD levels in Caucasians (n=77) and African-Americans (n=99). The genotype distribution among races differed at 13 SNPs. Nine SNPS were associated with circulating GPI-PLD levels in Caucasians but not African-Americans. These results suggest that genetic variation of GPLD1 appears to associate with circulating GPI-PLD levels. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

Adiposity has unique influence on the renin-aldosterone axis and blood pressure in black children.

OBJECTIVE: To comparatively examine the effects of adiposity on the levels of plasma renin activity (PRA), plasma aldosterone concentration (PAC), and aldosterone-renin ratio (ARR) in young black and white children. STUDY DESIGN: We prospectively assessed 248 black and 345 white children and adolescents. A novel analytical technique was used to assess the concurrent influences of age and body mass index (BMI) on PRA, PAC, and ARR. The estimated effects were depicted by colored contour plots. RESULTS: In contrast to whites, blacks had lower PRA (2.76 vs 3.36 ng/mL/h; P < .001) and lower PAC (9.01 vs 14.59 ng/dL; P < .001). In blacks, BMI was negatively associated with PRA (P = .001), consistent with an association with a more expanded plasma volume; there was no association with PAC. In whites, BMI was positively associated with PAC (P = .005); we did not detect a BMI-PRA association. The effects of BMI on ARR were directionally similar in the two race groups but more pronounced in blacks. Mean systolic blood pressure was greater in blacks with lower PRA (P < .01), higher PAC (P = .015), and higher ARR (P = .49). CONCLUSIONS: An increase in adiposity was associated with a suppressed PRA in blacks and an increase in PAC in whites. The unique relationship between adiposity and renin-aldosterone axis in blacks suggests the possible existence of a population-specific mechanism characterized by volume expansion, which could in turn enhance the influences of adiposity on blood pressure in black children and adolescents.

A consideration of genetic mechanisms behind the development of hypertension in blacks.

Hypertension is a more serious disease in blacks. The determinants of the blood pressure (BP) may be uniquely different from those in whites. The characteristic low-renin, salt-sensitive hypertension of blacks is consistent with the kidney reabsorbing additional sodium (Na), which leads to an expanded plasma volume that drives the BP. Mechanisms considered are genetically based. These include: (1) the intra-renal renin-angiotensin system (RAS), one based on molecular variations in angiotensinogen; (2) the Na, K, 2Cl cotransporter (NKCC2) and its regulators in the thick ascending limb, which are associated with a variety of phenotypes consistent with a more active cotransporter in blacks; and (3) the genes for MYH9 and APOL 1, which have been associated with kidney disease in blacks. To achieve a state of hypertension, an increase in Na uptake in proximal nephron regions may require a distal nephron that does not fully adjust due to less than adequate suppression of aldosterone production.

Race, sex, and the regulation of urine osmolality: observations made during water deprivation.

A more concentrated urine is excreted by blacks than whites and by men than women. The purpose of this study was to explore the physiological bases for the race and sex effects during water deprivation when osmoregulation is challenged and differences are amplified. Drinking water was withheld from 17 blacks (10 men) and 19 whites (9 men) for 24 h. Vasopressin (VP) levels and osmolality in plasma (P(osmol)) and urine (U(osmol)) were measured basally and then every 4 h. U(osmol) was higher in blacks at baseline (P = 0.01) and during water deprivation (P = 0.046). Before and during water deprivation, no differences were seen in levels of VP, P(osmol), or the VP-U(osmol) relationship between blacks and whites. Although VP levels were initially higher in men (P < 0.02 for samples collected over the first 12 h), over the last 12 h of water deprivation, U(osmol) was higher (P = 0.027) and more responsive to the level of VP (in terms of slopes, P = 0.0001) in women than men. Our results suggest that, after a period of water deprivation, there develops a sensitivity of the collecting duct to VP that is greater in women. Although U(osmol) is higher in blacks, the race difference in water conservation did not appear to result from differences in the level of VP or the sensitivity of the collecting duct to VP. Upstream effects such as Na(+) uptake in the thick ascending limb, with its ensuing effects on water reabsorption, need to be considered in future studies of the relationship of race to water conservation.

Age-Related Blood Pressure Sensitivity to Aldosterone in Blacks and Whites.

Aldosterone sensitivity, defined as the magnitude of the association of plasma aldosterone concentration with blood pressure (BP), seems to be a function of plasma volume. It increases as plasma renin activity decreases, and it is more significant in blacks but less so in whites. Age is a strong determinant of BP, and an increase in aldosterone sensitivity could contribute to the increase in BP. In the present study, we tested the hypothesis that aldosterone sensitivity increases with age. We used observational data collected from normotensive blacks and whites enrolled in a prospective cohort study. They were studied as children (248 blacks/357 whites) and again as young adults (74 blacks/125 whites) over an age range of 7 to 39 years. A varying-coefficient regression analysis was used to explore the influences of aldosterone on systolic BP. After controlling for body mass index, race, and sex, both plasma renin activity and plasma aldosterone concentration were lower in blacks, and their levels declined with age (P<0.001). In blacks, plasma aldosterone concentration decreased 0.25 ng/dL per year; in whites, plasma aldosterone concentration decreased 0.18 per year. Aldosterone's effect on BP, characterized by a smooth function of age, intensified as age increased, especially in blacks (P<0.01), suggesting an increased aldosterone sensitivity with age. In comparison to blacks, age-related changes in aldosterone sensitivity in whites were not statistically significant. These findings extend the rationale for targeting aldosterone in the treatment of hypertension, especially in blacks.

Functional characterization of polymorphisms in the kidney enhancer of the human renin gene.

The renin gene is regulated by an enhancer located 2.6 kb upstream of the transcription start site in the mouse and 11 kb upstream in humans. Despite extensive sequence conservation, the mouse renin enhancer is transcriptionally more active than the human renin enhancer. We report that the mechanism accounting for this is a result of sequence variation in the promoter proximal half-site of a retinoic-acid response element present in the enhancer. This sequence difference also prompted us to search for naturally occurring polymorphisms in the renin enhancer among normal and hypertensive human subjects. We sequenced the kidney enhancer from 90 samples derived from the Coriell Polymorphism Discovery Resource and 95 severely hypertensive Caucasian and African-American individuals. A single relatively frequent polymorphism (7, 2, and 7%, respectively in the Coriell, African-American, and Caucasian) was identified in the enhancer, one nucleotide downstream of the promoter distal half-site of the retinoic-acid response element. This variant was transcriptionally silent in transfection assays performed in renin-expressing As4.1 cells, a model of renal juxtaglomerular cells. A singleton polymorphism in the promoter was also identified in a single African-American individual. This polymorphism was located between binding sites for CBF1 and homeobox D10 but was also transcriptionally silent either in the presence or absence of the enhancer. Our study demonstrates the presence of silent polymorphisms in the renin promoter and enhancer, thus underscoring the critical importance of performing functional analyses before initiating expensive clinical studies seeking association between polymorphisms and complex diseases such as hypertension.

Studies of an association in boys of blood pressure and the Y chromosome.

BACKGROUND: Variations in the Y chromosome have shown significant, albeit inconsistent, associations with hypertension in men. Studies of peripubertal subjects might reveal more information on the origins of the Y chromosome's influence on blood pressure (BP). In the current study, we examined the association of a HindIII restriction site on the Y chromosome with BP in a cohort of young men. METHODS: Pubertal growth-based analyses were performed in 80 unrelated males with multiple measurements spanning time points beginning before and extending to after their pubertal growth. Blood pressure, height, and weight were measured approximately every 6 months. The period of pubertal growth was used to approximate the time for puberty. The association of the HindIII restriction site to systolic and diastolic BP was determined using a mixed model ANOVA. RESULTS: Estimated systolic and diastolic BPs were higher in HindIII(-) males in the period before, as well as in the period after pubertal growth (systolic BP 2.6 +/- 1.3 mm Hg higher, P < .05), and diastolic BP 2.3 +/- 1.2 mm Hg higher, P = .050). In addition, HindIII(-) males were younger at onset of peak height velocity (12.7 +/- 0.1 v 13.3 +/- 0.1 years, P < .001). In African Americans, an earlier age of maximal height velocity was associated with a higher systolic and diastolic BP (P < .05 and .02, respectively). CONCLUSIONS: The results suggest that variations in genes on the Y chromosome may affect BP in peripubertal males, possibly even before onset of puberty.

Association of Circulating Renin and Aldosterone With Osteocalcin and Bone Mineral Density in African Ancestry Families.

Hypertension is associated with accelerated bone loss, and the renin-angiotensin-aldosterone system is a key regulator of blood pressure. Although components of this system are expressed in human bone cells, studies in humans are sparse. Thus, we studied the association of circulating renin and aldosterone with osteocalcin and bone mineral density. We recruited 373 African ancestry family members without regard to health status from 6 probands (mean family size: 62 and relative pairs: 1687). Participants underwent a clinical examination, dual-energy x-ray absorptiometry, and quantitative computed tomographic scans. Renin activity, aldosterone concentration, and osteocalcin were measured in fasting blood samples. Aldosterone/renin ratio was calculated as aldosterone concentration/renin activity. All models were analyzed using pedigree-based variance components methods. Full models included adjustment for age, sex, body composition, comorbidities, lifestyle factors, blood pressure, and antihypertensive medication. Higher renin activity was significantly associated with lower total osteocalcin and with higher trabecular bone mineral density (both P<0.01). There were also significant genetic correlations between renin activity and whole-body bone mineral density. There were no associations with aldosterone concentration in any model and results for aldosterone/renin ratio were similar to those for renin activity. This is the first study to report a significant association between renin activity and a marker of bone turnover and bone mineral density in generally healthy individuals. Also, there is evidence for significant genetic pleiotropy and, thus, there may be a shared biological mechanism underlying both the renin-angiotensin-aldosterone system and bone metabolism that is independent of hypertension.

Onset of overweight during childhood and adolescence in relation to race and sex.

Overweight [body mass index (BMI) percentile > or = 95th] in children has become a major public health problem. The age when overweight begins and how it progresses are mostly unknown. Such information would be important for the optimal timing of prevention. We conducted a survival analysis on time to overweight and compared survival curves by race and sex. Data from a cohort of 924 children recruited from schools in Indianapolis, IN, were analyzed. Blacks were at greater risk for becoming overweight than whites. Similar findings were obtained when at risk of overweight (BMI percentile > or = 85th and <95th) and overweight were considered as a single category. Twenty-five percent of blacks were overweight or at risk of overweight at or before age 7 yr, whereas it was age 11 yr in white females and age 10 yr in white males when 25% became overweight or were at risk of becoming overweight. The overall overweight-free survival curve for black females was significantly different from that for white females (P < 0.001), and black males were significantly different from white males (P = 0.04). There was no sex difference. The time to overweight during childhood and adolescence varies by race, indicating the need for race-specific timing of interventions.

The change in blood pressure during pubertal growth.

Blood pressure (BP) in children may increase more during puberty. Using a cohort of children where BP and body size had been closely monitored, we compared the rates of change in BP during the 3-yr period before puberty, during puberty ( approximately 4.5-yr period), and the 3-yr period after puberty. Because there was no specific staging information with respect to puberty, we used pubertal growth (PG) as a surrogate of puberty. The latter was determined from serial measurements of height. All subjects (n = 151) were followed from before the period of PG to the period after PG; none were related. An age-dependent increase in systolic BP in the pre-PG period was similar regardless of sex or race. During PG, systolic BP in males increased three to six times faster than in the pre-PG period. In females, systolic BP increased less than in males during PG but still increased two to four times faster than in the pre-PG period. The increase in males was significantly greater than in females (P < 0.001). Post-PG changes in BP were similar to changes in pre-PG BP. In summary, PG was associated with profound increases in systolic BP. There were noticeably greater increments in males than in females consistent with the emergence of the well known sexual dimorphism in BP.

Racial differences in calcium retention in response to dietary salt in adolescent girls.

BACKGROUND: Sodium is an important determinant of urinary calcium excretion, and race is an important determinant of calcium retention. The effect of dietary sodium on calcium retention and the influence of race have not been studied in adolescence, the life stage during which peak bone mass is accrued. OBJECTIVE: The study reported here was undertaken to compare racial differences in calcium retention as a function of dietary salt intake. DESIGN: A total of 35 adolescent girls (22 black and 13 white) participated in two 20-d metabolic summer camps, separated by 2 wk, that simulated a free-living environment. The effect of changes in dietary sodium on calcium retention was tested in a randomized-order, crossover design with 2 concentrations of sodium-1.30 g/d (57 mmol/d) and 3.86 g/d (168 mmol/d)-and a constant calcium intake of 815 mg/d (20 mmol/d). RESULTS: Both race and sodium intake significantly affected calcium retention (P < 0.01). Calcium retention was significantly greater in black girls than in white girls, regardless of dietary sodium intake (P < 0.001). The high-sodium diet significantly reduced calcium retention in both whites and blacks (P < 0.01), primarily through a decrease in net calcium absorption. Black girls excreted significantly less calcium in the urine than did white girls, regardless of diet (P < 0.05). CONCLUSIONS: Calcium retention is significantly greater in black girls than in white girls but is significantly reduced in girls of both races in response to salt loading.

Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients.

OBJECTIVES: The purpose of this study was to evaluate the efficacy and tolerability of monotherapy with the selective aldosterone blocker eplerenone in both black and white patients with hypertension. BACKGROUND: Essential hypertension and cardiovascular-renal-target organ damage is more prevalent in black than white adults in the U.S. METHODS: Black (n = 348) and white (n = 203) patients with mild-to-moderate hypertension were randomized to double-blind treatment with eplerenone 50 mg, the angiotensin II receptor antagonist losartan 50 mg, or placebo once daily. Doses were increased if blood pressure remained uncontrolled. The primary end point was change in mean diastolic blood pressure (DBP) after 16 weeks of therapy. RESULTS: Adjusted mean changes from baseline in DBP were -5.3 +/- 0.7, -10.3 +/- 0.7, and -6.9 +/- 0.6 mm Hg in the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean +/- SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan). In black patients, DBP decreased by -4.8 +/- 1.0, -10.2 +/- 0.9, and -6.0 +/- 0.9 mm Hg for the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean +/- SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan), whereas in white patients, DBP decreased by -6.4 +/- 1.0, -11.1 +/- 1.1, and -8.4 +/- 1.0 mm Hg, respectively (p = 0.001 eplerenone vs. placebo, p = 0.068 for eplerenone vs. losartan). For reduction of systolic blood pressure (SBP), eplerenone was superior to placebo and losartan in all patients combined and in black patients, and was superior to placebo in white patients. Eplerenone was as effective as losartan in reducing SBP and DBP in the high renin patient, but more effective than losartan in the low renin patient. Similarly, eplerenone was at least as effective as losartan in patients with differing baseline levels of aldosterone. Both eplerenone and losartan were well tolerated. CONCLUSIONS: The antihypertensive effect of eplerenone was equal in black and white patients and was superior to losartan in black patients.

Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes.

Plasminogen activator inhibitor-1 (PAI-1) is an anti-thrombolytic factor that also promotes tissue fibrosis. Under certain conditions, exposure to aldosterone can result in cardiac fibrosis by an unknown mechanism. In the current study, we tested the hypothesis that PAI-1 is a mediator of aldosterone's fibrotic effects. Aldosterone increased levels of PAI-1 mRNA and protein in the H9c2 rat cardiac cell line, responses that could be blocked by the mineralocorticoid receptor (MR) antagonist spironolactone. Confocal microscopy confirmed an effect of aldosterone to increase PAI-1 expression with reversal by spironolactone. Aldosterone also increased PAI-1 expression in neonatal rat cardiomyocytes, which was again blocked by spironolactone. In the neonatal cardiomyocytes (but not the H9c2 cells), anti-transforming growth factor-beta1 antibody inhibited the PAI-1 response to aldosterone. In summary, aldosterone directly increased PAI-1 expression in two different cardiac muscle cell types, an effect that was dependent on MR. In the neonatal cells, there appeared to be a requirement for transforming growth factor-beta1.

Non-genomic effects of aldosterone: new actions and questions.

Although the classical actions of aldosterone are mediated through genomic pathways, there is a growing recognition of important nongenomic responses to aldosterone. New data are presented from two laboratories showing a nongenomic effect of aldosterone to activate protein kinase C (PKC) in heart and kidney. Among the actions of PKC is the stimulation of transcription factors, raising the question of whether there is an inter-relationship of nongenomic with genomic influences--aldosterone induced nongenomic effects might modulate genomic effects. This expanded role of aldosterone will require exploration in future studies.

Shockwave lithotripsy: dose-related effects on renal structure, hemodynamics, and tubular function.

BACKGROUND AND PURPOSE: Shockwave lithotripsy (SWL) predictably damages renal tissue and transiently reduces function in both kidneys. This study characterized the effects on renal function of a supraclinical dose of shockwaves (SWs) (8000) in porcine kidneys and tested the hypothesis that such excessive treatment would intensify and prolong the resulting renal impairment. MATERIALS AND METHODS: Pigs aged 6 to 7 weeks were anesthetized and assigned to one of three groups. Groups 1 (N=8) and 2 (N=6) each received 8000 SWs at 24 kV (Dornier HM3) to the lower-pole calix of one kidney. Group 3 (7 pigs) received sham treatment. Renal function was monitored for the first 4 hours after SW treatment in Group 1 and for 24 hours in Group 2. Plasma renin activity was measured in Groups 2 and 3. RESULTS: The renal lesions produced by 8000 SWs comprised 13.8%+/-1.4% of the renal mass. In the 4-hour protocol, this injury was associated with marked reduction of the glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary sodium excretion in both kidneys, although fractional sodium excretion was reduced only in the shocked kidneys. In the 24-hour protocol, GFR and RPF remained below baseline in shocked kidneys at 24 hours. Evidence of progressive ischemic injury was noted in shocked tissue at 24 hours after SW treatment. CONCLUSIONS: These findings support the hypothesis that the severity of the renal injury caused by SWL is related to the number of SWs administered and demonstrate the connection in this relation between renal structure and function.

Activity of 11beta-hydroxysteroid dehydrogenase type 2 in normotensive blacks and whites.

BACKGROUND: Salt-sensitive hypertension occurs more commonly in Blacks than in Whites. A decrease in activity of the enzyme 11betaHSD2 that results in overstimulation of the mineralocorticoid receptor by cortisol could contribute to greater retention of sodium in Blacks. We tested the hypothesis that less activity of the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is present in Blacks than in Whites. METHODS: Eighty-nine subjects (42 Whites and 47 Blacks), ages 12 to 24 years were recruited from a young cohort that was followed longitudinally in a study of blood pressure regulation. For purposes of study, they were admitted to the General Clinical Research Center. Excretion of tetrahydrocortisol (THF), 5alpha-THF, and tetrahydrocortisone (THE) was measured in 12-hour overnight urine collections. In vivo 11betaHSD2 activity was estimated from the urinary (THF + 5alpha-THF)/THE) ratio. RESULTS: Blacks appeared to retain more sodium as evidenced by a lower level of 2-hour upright plasma aldosterone (P<.001) and marginally lower plasma renin activity (P=.06). The (THF + 5alpha-THF)/THE ratio in Blacks and Whites was similar: 0.91 +/- 0.41 (standard deviation), 0.86 +/- 0.52, 1.13 +/- 0.36, and 0.66 +/- 0.26, in White males, White females, Black males, and Black females, respectively; P=.35 for an overall effect of race. CONDUSION: 11betaHSD2 activity appears to be similar in Blacks and Whites and probably contributes minimally, if at all, to race differences in sodium retention.