Recent aspects in the genetic renal mechanisms involved in hypertension

The kidney plays an important role in the blood pressure regulation primarily by modulating tubular sodium reabsorption. Various hormones, vasoactive peptides, autacoids and transporters or channels in renal tubules are involved in this process. Genes associated with renal tubular sodium handling are possibly related to the development of hypertension. Genes of the renin-angiotensin-aldosterone system are thought to be especially important as causal genes of hypertension. Na-K-ATPase, biochemically equal to Na pump, exists on the basolateral membrane of renal epithelial cells. It plays a central role in Na reabsorption and creates a driving force for transepithelial transport. Na-K-ATPase activity is regulated by adducin, a membrane-bound skeletal protein, as well as by several hormones such as dopamine, endogenous ouabain-like factor or cytochrome P450 metabolites. Genes of these factors involved in Na-K-ATPase regulation should be related to the development of hypertension. The endothelin system, atrial natriuretic peptide and nitric oxide regulate the tonus of blood vessels as well as renal sodium excretion. Several reports have indicated that genes of these substances are crucial in the pathogenesis of hypertension.     

Dissection of a quantitative trait locus for genetic hypertension on rat chromosome 10.

We have previously identified a locus on rat chromosome 10 as carrying a major hypertension gene, BP/SP-1. The 100:1 odds support interval for this gene extended over a 35-centimorgan (cM) region of the chromosome that included the angiotensin I-converting enzyme (ACE) locus as demonstrated in a cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKY-0HD) rat. Here we report on the further characterization of BP/SP-1, using a congenic strain, WKY-1HD. WKY-1HD animals carry a 6-cM chromosomal fragment genotypically identical with SHRSPHD on chromosome 10, 26 cM away from the ACE locus. Higher blood pressures in the WKY-1HD strain compared with the WKY-0HD strain, as well as absence of linkage of the chromosome 10 region to blood pressure in an F2 (WKY-1HD x SHRSPHD) population suggested the existence of a quantitative trait locus, termed BP/SP-1a, that lies within the SHRSP-congenic region in WKY-1HD. Linkage analysis in the F2 (WKY-0HD x SHRSPHD) cross revealed that BP/SP-1a is linked to basal blood pressure, whereas a second locus on chromosome 10, termed BP/SP-1b, that maps closer to the ACE locus cosegregates predominantly with blood pressure after exposure to excess dietary NaCl. Thus, we hypothesize that the previously reported effect of BP/SP-1 represents a composite phenotype that can be dissected into at least two specific components on the basis of linkage data and congenic experimentation. One of the loci identified, BP/SP-1a, represents the most precisely mapped locus affecting blood pressure that has so far been characterized by random-marker genome screening.     

N-domain angiotensin I-converting enzyme with 80 kDa as a possible genetic marker of hypertension

We have previously described angiotensin I-converting enzyme (ACE) forms in urine of normotensive (190 and 65 kDa) and hypertensive patients (90 and 65 kDa, N-domain ACEs). Based on the results described above, experimental and genetic models of hypertension were investigated to distinguish hemodynamic and genetic influence on the generation of ACE profile in urine: Wistar-Kyoto and Brown Norway rats (WKY and BN), spontaneously and stroke-prone spontaneously hypertensive rats (SHR and SHR-SP), one kidney/one clip rats (1K1C), deoxycorticosterone acetate (DOCA) salt-treated and untreated rats, and enalapril-treated SHR (SHRen). Two peaks with ACE activity were separated from the urine of WKY and BN rats submitted to an AcA-44 column, WK-1/BN-1 (190 kDa), and WK-2/BN-2 (65 kDa), as described for urine of normotensive subjects. The same results were obtained for urine of 1K1C and DOCA salt-treated and untreated rats, analyzed to evaluate the influence of hemodynamic factors in the ACE profile in urine. The urine from SHR, SHR-SP, and SHRen presented 80 (S-1, SP-1, Sen-1) and 65 (S-2, SP-2, Sen-2) kDa ACE forms, differing from the urine profile of normotensive rats, but similar to that described for hypertensive patients. The presence of 80 kDa ACE in urine of SHR, SHR-SP, and SHRen and its absence in urine of experimental hypertensive rats (1K1C and DOCA salt) support the hypothesis that this enzyme could be a possible genetic marker of hypertension. Taken together, our results provide evidence that ACE forms with 90/80 kDa isolated from the urine of hypertensive subjects and genetic hypertensive animals behaves as a possible genetic marker of hypertension and not as a marker of high blood pressure.     

Defect in the excretion of a vasoactive polypeptide fraction A possible genetic marker of primary hypertension

A polypeptide fraction isolated from the urine of normotensive subjects lowers the blood pressure (BP) in a rabbit bioassay (mean BP decrease 33.8% +/- 0.6%, SEM). Patients with primary hypertension exhibit reduced or no activity (mean BP decrease 8.8% +/- 1.2%). In contrast, patients with secondary forms of hypertension show activity like normotensives (mean BP decrease 33.4% +/- 1.0%). The results of the bioassay in the two patient groups correlate well with the family incidence of hypertension (68% and 37% for primary and secondary hypertension respectively). Cases with borderline hypertension fall into two groups; a larger one with vasoactivity inthe bioassay and lower family incidence of hypertension; and a smaller group reacting like patients with primary hypertension. Only the latter group may represent an initial stage of primary hypertension. In normotensive children and young men, an inactive fraction was found in 31% and 28% respectively. These inactive groups had twice the family incidence of hypertension compared to the groups with vasoactivity. These results suggest the existence of a possible genetic marker of primary hypertension and may offer the possibility to detect the disease before its manifestation.     

Vasopressin as a possible contributor to hypertension

The role of vasopressin as a pressor agent to the hypertensive process was examined. Vasopressin plays a major role in the pathogenesis of DOCA-salt hypertension, since the elevation of blood pressure was not substantial in the rats with lithium-treated diabetes insipidus after DOCA-salt treatment. Administration of DDAVP which has antidiuretic action but minimal vasopressor effect failed to increase blood pressure to the levels observed after administration of AVP. Furthermore, the pressor action of vasopressin appears to be important in the development of this model of hypertension, since the enhanced pressor responsiveness to the hormone was observed in the initial stage of hypertension. Increased secretion of vasopressin from neurohypophysis also promotes the function of the hormone as a pathogenetic factor in hypertension. An unproportional release of vasopressin compared to plasma osmolality may be induced by the absence of an adjusting control of angiotensin II forming and receptor binding capacity for sodium balance in the brain. However, the role of vasopressin remains to be determined in human essential hypertension.     

Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis

Primary systemic amyloidosis (AL) is a plasma cell (PC) dyscrasia with clinical similarities to multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), but its molecular basis is poorly understood. Translocations at the immunoglobulin heavy-chain (IgH) locus, 14q32, are likely early genetic events in both MM and MGUS and involve several nonrandom, recurrent, partner chromosomes such as 11q13, 16q23, and 4p16.3. Given the similarities between MM, MGUS, and AL, bone marrow clonal PCs were evaluated in 29 patients with AL using interphase fluorescence in situ hybridization (FISH) combined with immunofluorescence detection of the cytoplasmic light-chain (cIg-FISH) for the presence of 14q32 translocations and the t(11;14)(q13;q32). Of 29 patients studied, 21 (72.4%) showed results compatible with the presence of a 14q32 translocation, and 16 (76.2%) of those had translocation (11;14)(q13;q32) for an overall prevalence of the abnormality of 55%. IgH translocations are common in AL, especially the t(11;14)(q13;q32).     

Modulation of intravariceal pressure with pentoxifylline: a possible new approach in the treatment of portal hypertension

Objective: In this study the effect of the hemorheological agent pentoxifylline on the pressure of esophageal varices was investigated in portal hypertensive cirrhotic patients.
Methods: Intravariceal pressure was measured endoscopically using the direct puncture technique in 20 patients. Measurements were obtained under baseline conditions and 30 min after double-blind administration of pentoxifylline (1.4 mg/kg BW, n = 10 patients) or an indentical volume of NaCl 0.9% solution (n = 10 patients).
Results: Under baseline conditions, intravariceal pressure was similar in pentoxifylline and placebo groups (17.3 ± 5.5 mm Hg vs 18.8 ± 4.6 mm Hg, respectively;   p = N.S.  ). Placebo administration had no significant effect on intravariceal pressure (18.8 ± 4.6 mm Hg vs 18.3 ± 4.1 mm Hg;   p = N.S.  ). In contrast, pentoxifylline caused a highly significant reduction of intravariceal pressure, (from 17.3 ± 5.5 mm Hg to 11.4 ± 5.9 mm Hg;   p = 0.0001  ), the overall mean reduction being 36.1 ± 14.1% mm Hg.
Conclusion: We concluded that pentoxifylline, by reducing blood flow viscosity, caused a significant decrease in variceal pressure in patients suffering from portal hypertension.     

Multiple mechanisms involved in obesity-induced hypertension

Obesity and hypertension are two major cardiovascular risk factors gaining epidemic proportions in our modern world. The interplay between hypertension, obesity and their major detrimental outcome, cardiovascular disease, is multifaceted and can be represented as the three corners of a triangle. Obesity and hypertension both lead to cardiovascular complications. In addition, obesity per se can promote hypertension. In turn, cardiovascular diseases can also predispose to obesity and hypertension. Low levels of physical activity due to a weakened heart promote weight gain. Endothelial, vascular and renal dysfunctions, all consequences of high blood pressure, further worsen hypertension. The loop of mutually amplifying detrimental effects is thus closed: a 'vicious triangle' is established. The association between obesity and hypertension was recognised and described almost a century ago, but the mechanisms that underlie this connection are still not fully understood. Vasoconstriction and sodium retention seem to be the cornerstones of the obesity-hypertension puzzle. However, pathways possibly leading to vasoconstriction and sodium retention are numerous. Evidence has been gathered that hyperleptinaemia, hyperinsulinaemia and elevated free fatty acids may induce sympathetic activation and vasoconstriction. The latter is further potentiated by insulin resistance and endothelial dysfunction. Positive sodium balance and ensuing volume expansion may be due to increased renal tubular sodium reabsorption induced by sympathetic stimulation, insulin or by a hyperactive renin-angiotensin system. All enumerated factors act together toward a state of permanently elevated blood pressure.     

Cilazapril, a new ACE inhibitor, in severe arterial hypertension]

We assessed the efficacy and safety of cilazapril, alone or in combination with hydrochlorothiazide. It was an open trial, that included 14 patients with or more 114 mmHg of diastolic arterial tension. On the first stage of 25 days, the arterial tension was normalized in 5 patients with 10 mg of cilazapril and 7 patients when hydrochlorothiazide was added, 2 patients did not respond. On the second stage of 52 weeks, of the 12 patients whose diastolic arterial tension was normalized, 2 patients remained with normal arterial tension with cilazapril, 5 when hydrochlorothiazide was added and the rest 5 patients did not respond. No undesirable side effects were detected, nor abnormalities in the laboratory tests. The long-term benefit obtained on 50% of patients make evident the usefulness of cilazapril in severe arterial hypertension. Its administration once a day and the absence of side effects increase the interest of its use.     

AHSP and beta-thalassemia: a possible genetic modifier

The identification of defectives genes underlying inherited diseases has made it clear that patients with the same genotype can have variable clinical expression. Suggestions proposing that the protein AHSP, a alpha-globin specific chaperone could influence disease severity in patients with beta-thalassemia, an inherited disorder characterized by a quantitative deficiency of beta-globin genes. This article presents a review of the AHSP gene structure, function and expression. A discussion of the AHSP gene acknowledgements is presented with an overview of the possible genetic modifier function of AHSP on beta-thalassemia pathophysiology.     

Aldosterone-related genetic effects in hypertension

Our basic understanding of Na+ transport mechanisms provides unique insights into epithelial transport processes. Unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect Na+ balance, resulting in both Na+ retaining and Na+ wasting conditions. A major focus has been the epithelial sodium channel (ENaC), which can be activated by mutations (eg, Liddle’s syndrome), changes in the response to mineralocorticoids (apparent mineralocorticoid excess syndrome), or production of mineralocorticoids (glucocorticoid-remediable aldosteronism). As a result, we now have clearly defined Mendelian syndromes in which ENaC activity is "dysregulated." This dysregulation leads to systemic hypertension associated with suppressed plasma renin activity, which can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low-renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension.     

Klotho locus, metabolic traits, and serum hemoglobin in hospitalized older patients: a genetic association analysis

Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65–99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity.     

Context-dependent genetic effects in hypertension

There is a growing frustration with the limitations and inconsistencies of single locus candidate gene association and linkage studies. This frustration is exacerbated by the knowledge that a large influx of genotypic and gene expression data is expected to emerge over the next 5 years, and we are not prepared for the type of multigenic conceptual framework that will be necessary to analyze that data. A review of the hypertension genetic literature reveals substantial evidence for the importance of both genetic and environmental contexts on the mapping between single locus polymorphisms and risk of disease. These trends indicate that the current reliance on simple single gene studies to elucidate the complex etiology of hypertension needs to undergo some kind of transformation. It is suggested that even a minor shift to a more systematic investigation of context-dependent effects will increase our understanding of the multidimensional genetic and environmental realities underneath current studies. This shift is also necessary if we are to gain a deeper understanding of the specific ways in which an individual’s risk of hypertension is a consequence of the interactions among genes and environments.     

Prostasin: a possible candidate gene for human hypertension

BackgroundProstasin, a serine protease, is suggested to be a novel mechanism regulating the epithelial sodium channel (ENaC) expressed in the distal nephron. This study aimed to evaluate whether the human prostasin gene is a novel candidate gene underlying blood pressure (BP) elevation.MethodsIn a sample of healthy African-American (AA) and European-American (EA) twin subjects aged 17.6 +/- 3.3 years (n = 920, 45% AAs), race-specific tagging single-nucleotide polymorphisms (tSNPs) were identified to tag all the available SNPs +/- 2 kb up- and downstream of the prostasin gene from HapMap at r(2) of 0.8-1.0. Selection yielded four tSNPs in AAs and one in EAs, with one tSNP (rs12597511: C to T) present in both AAs and EAs.ResultsFor rs12597511, CT and TT genotypes exhibited higher systolic BP (SBP) than CC genotype (115.9 +/- 1.1 mm Hg vs. 113.7 +/- 0.6 mm Hg, P = 0.025 (AAs); and 110.7 +/- 0.5 mm Hg vs. 109.6 +/- 0.6 mm Hg, P = 0.115 (EAs)). CT and TT genotypes compared with CC genotype showed a significant increase in diastolic BP (DBP) in both racial groups (62.5 +/- 0.7 mm Hg vs. 60.4 +/- 0.4 mm Hg, P = 0.003 (AAs); and 58.2 +/- 0.3 mm Hg vs. 56.7 +/- 0.4 mm Hg, P = 0.007 (EAs)). Furthermore, there was an increase in radial pulse wave velocity (PWV) in subjects with CT and TT genotype as compared with those with CC genotype (6.5 +/- 0.1 vs. 6.1 +/- 0.1 m/s, P < 0.0001) (EAs); and 6.7 +/- 0.1 vs. 6.6 +/- 0.1 m/s, P = 0.354 (AAs)). Analyses combining AAs and EAs consistently demonstrated a statistical significance of rs12597511 on all the phenotypes including SBP/DBP and PWV.ConclusionGenetic variation of the prostasin gene may be implicated in the development of hypertension in youths.American Journal of Hypertension (2008). doi 10.1038/ajh.2008.224American Journal of Hypertension (2008); 21, 9, 1028-1033. doi 10.1038/ajh.2008.224.     

Mediators involved in HIV-related pulmonary arterial hypertension

HIV-related pulmonary arterial hypertension (PAH) is one of the long-term complications of HIV infection that has become increasingly apparent in recent years. The clinical presentation and underlying pathology of PAH in HIV is similar to that in other forms of the disease, although there are data to suggest subtle differences, such as a greater inflammatory component in the HIV-related form. Advances continue to be made in defining the underlying pathogenesis of PAH, but the overall processes leading to vascular dysfunction and remodeling remain unclear. It would appear that PAH has a multifactorial etiology, with various risk factors--probably acting on an underlying genetic predisposition--that lead to the pulmonary vascular dysfunction that characterizes the disease. A range of growth factors, chemokines, cytokines and other inflammatory mediators, together with mediators involved in vasoconstriction and dilation, have been implicated in the pulmonary vascular remodeling resulting from this dysfunction. An increased understanding of the processes and factors involved in PAH has led to the development of new therapeutic strategies that have improved the management of various forms of PAH, including PAH associated with HIV (HIV-PAH). Recent results from studies into other potential mediators of PAH offer the possibility of new targets for therapy in this progressive and serious condition.