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Biomedical subjects

H Haller

Publications and source records attributed to H Haller.

At least 145 records · Page 8Linked to original sources
PubMed1997

Leukocyte infiltration and ICAM-1 expression in two-kidney one-clip hypertension.

How an increase in blood pressure, in and of itself, induces hypertensive nephrosclerosis is unclear. In an earlier study we found that leukocyte infiltration, proximal tubular cell proliferation, matrix deposition and interstitial fibrosis occur in the unclipped kidney of 2 K 1 C Goldblatt hypertensive rats. In this study we tested the hypothesis that the cell surface adhesion molecule ICAM-1 is expressed on the vascular endothelium and tubular epithelium of unclipped kidneys at 4 weeks. As a positive control, we examined the clipped kidney as well. We found that systolic blood pressure was significantly elevated in renovascular hypertensive rats compared to sham-operated controls after 4 weeks (198 +/- 5 mmHg vs 121 +/- 2 mmHg, P < 0.001). Furthermore, quantitative (densitometry) measurements showed that ICAM-1 expression on vascular endothelium and on tubular cells was significantly increased in unclipped kidneys compared to controls (P < 0.05). The same was true for monocyte and granulocyte infiltration (P < 0.05). These same variables were even more prominent in the clipped kidneys, compared to unclipped and control kidneys (P < 0.05). Our data show that ICAM-1 is expressed in unclipped kidneys exposed to hypertension as well as in clipped kidneys exposed to ischemia. We suggest that mechanical injury induced by increased blood pressure is responsible for an inflammatory adhesion molecule-mediated response and concomitant renal injury.

Animals↗
PubMed1997

From totipotent embryonic stem cells to spontaneously contracting smooth muscle cells: a retinoic acid and db-cAMP in vitro differentiation model.

Vascular smooth muscle cell (VSMC) differentiation is important in understanding vascular disease; however, no in vitro model is available. Totipotent mouse embryonic stem (ES) cells were used to establish such a model. To test whether the ES cell-derived smooth muscle cells expressed VSMC-specific properties, the differentiated cells were characterized by 1) morphological analysis, 2) gene expression, 3) immunostaining for VSMC-specific proteins, 4) expression of characteristic VSMC ion channels, and 5) formation of [Ca2+]i transients in response to VSMC-specific agonists. Treatment of embryonic stem cell-derived embryoid bodies with retinoic acid and dibutyryl-cyclic adenosine monophosphate (db-cAMP) induced differentiation of spontaneously contracting cell clusters in 67% of embryoid bodies compared with 10% of untreated controls. The highest differentiation rate was observed when retinoic acid and db-cAMP were applied to the embryoid bodies between days 7 and 11 in combination with frequent changes of culture medium. Other protocols with retinoic acid and db-cAMP, as well as single or combined treatment with VEGF, ECGF, bFGF, aFGF, fibronectin, matrigel, or hypoxia did not influence the differentiation rate. Single-cell RT-PCR and sequencing of the PCR products identified myosin heavy chain (MHC) splice variants distinguishing between gut and VSMC isoforms. RT-PCR with VSMC-specific MHC primers and immunostaining confirmed the presence of VSMC transcripts and MHC protein. Furthermore, VSMC expressing MHC had typical ion channels and responded to specific agonists with an increased [Ca2+]i. Here we present a retinoic acid + db-cAMP-inducible embryonic stem cell model of in vitro vasculogenesis. ES cell-derived cells expressing VSMC-specific MHC and functional VSMC properties may be a suitable system to study mechanisms of VSMC differentiation.

Animals↗
PubMed1997

Effects of pinacidil on K+ channels in human coronary artery vascular smooth muscle cells.

We investigated pinacidil-activated K+ currents in vascular smooth muscle cells (VSMC) from human coronary arteries with the patch-clamp method. In 19 of 54 VSMC, pinacidil (1 and 20 microM) induced a large, nonrectifying, outward current [IK(ATP)] and increased voltage-dependent outward K+ currents [IK(Ca)] positive to voltages of -25 mV. The pinacidil-induced (1 microM) IK(ATP) was blocked by glibenclamide (3 microM) but was not affected by iberiotoxin (100-300 nM). Pinacidil activated up to 150 functionally active ATP-dependent K+ channels (KATP channels) per cell with a single-channel conductance of approximately 17 pS at physiological membrane potentials (between -80 and -30 mV) and K+ gradients (6 mM/130 mM). In 26 of 54 VSMC, on the other hand, pinacidil (1-20 microM) failed to induce IK(ATP) but increased IK(Ca). This current was completely blocked by iberiotoxin (100-300 nM) and tetraethylammonium (1 mM) but not by glibenclamide (3 microM). The single-channel conductance of the channel underlying IK(Ca) was approximately 150 +/- 16 pS between -10 and +30 mV, consistent with large-conductance, maxi Ca(2+)-activated, K+ channels (BKCa channels). We conclude that pinacidil is a nonselective K+ channel opener targeting KATP and BKCa channels. Furthermore, the conductance of KATP channels in human coronary arteries is likely to be small under physiological conditions.

Animals↗
PubMed1997

Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients.

Endothelial cell activation is important in the pathogenesis of preeclampsia; however, the nature of the activation is unknown. We investigated 22 patients with preeclampsia. 29 normotensive pregnancies, and 18 nonpregnant women to test the hypothesis that serum from preeclamptic patients induces expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and stimulates intracellular free calcium concentrations [Ca2+]i in cultured endothelial cells. We then asked whether the corresponding integrin adhesive counter receptors lymphocyte function-associated antigen-1 (CD11a/CD18), macrophage-1 antigen (CD11b/CD18), p150,95 (CD11c/CD18), and very late activation antigen-4 (CD49/CD29) are increased in patients with preeclampsia. In the pregnant women, the measurements were conducted both before and after delivery. Integrin expression was measured by fluorescent antibody cell sorting analysis using monoclonal antibodies. ICAM-1 and VCAM-1 were analyzed on endothelial cells by enzyme-linked immunosorbent assay. [Ca2+]i was measured with fura 2. Serum from preeclamptic patients increased endothelial cell ICAM-1 expression but not VCAM-1 expression. Preeclamptic patients' serum also increased [Ca2+]i in endothelial cells compared with serum from normal nonpregnant or normal pregnant women. Endothelial cell [Ca2+]i concentrations were correlated with the ICAM-1 expression in preeclamptic patients (r = .80, P < .001) before but not after delivery. Expression of the integrin counter receptors on leukocytes was similarly increased in preclampsia and normal pregnancy compared with the nonpregnant state. The expression decreased significantly after delivery in both groups. Our results demonstrate that serum from preeclamptic women induces increased ICAM-1 surface expression on endothelial cells, while the expression of the integrin counterreceptors was not different. The effect on endothelial cells may be related to an increase in [Ca2+]i. The effect on cultured endothelial cells and the rapid decrease after delivery suggests the presence of a circulating serum factor which increases endothelial cell [Ca2+]i and enhances adhesion molecule expression.

Adult↗
PubMed1997

High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha.

Endothelial cell permeability is impaired in diabetes mellitus and may be increased by high extracellular glucose concentrations. High glucose activates protein kinase C (PKC), a family of kinases vital to intracellular signaling. We tested the hypothesis that high glucose concentration activates PKC in endothelial cells and leads to an increase in endothelial cell permeability via distinct PKC isoforms. Porcine aortic endothelial cells were used, and the PKC isoforms alpha, delta, epsilon, zeta, and theta were identified in these cells. Glucose caused a rapid dose-dependent increase in endothelial cell permeability, with an EC50 of 17.5 mmol/L. Phorbol 12-myristate 13-acetate (TPA) induced an increase in permeability very similar to that elicited by glucose. The effect of glucose and TPA was totally reversed by preincubating the cells with the PKC inhibitors staurosporine (10(-8) mol/L) and Goe 6976 (10(-8) mol/L). Downregulation of PKC by preincubation with TPA for 24 hours also abolished the effect of glucose and TPA on endothelial cell permeability. High glucose (20 mmol/L) caused an increase in PKC activity at 2, 10, and 30 minutes. Cell fractionation and Western blot analysis showed a glucose-induced translocation of PKC alpha and PKC epsilon. Confocal microscopy confirmed the translocation and showed an association of PKC alpha and PKC epsilon with nuclear structures and the cell membrane. Specific antisense oligodesoxynucleotides (ODNs) against PKC alpha reduced the expression of the isoform, abolished the effects of glucose on endothelial cell permeability completely, and reduced the TPA effect significantly. In contrast, specific antisense ODNs against PKC epsilon had no effect on glucose-induced permeability and only a minor effect on the TPA-induced increase in permeability. We conclude that an increase in extracellular glucose leads to a rapid dose-dependent increase in endothelial cell permeability via the activiation of PKC and that this effect is mediated by the PKC isoform alpha.

Animals↗
PubMed1997

Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly.

BACKGROUND AND PURPOSE: Autosomal dominant hypertension with brachydactyly features severe hypertension that causes stroke usually before the age of 50 years. We recently characterized the hypertension as featuring normal renin, aldosterone, and catecholamine responses and mapped the gene responsible to chromosome 12p. Since angiography in an affected subject had earlier shown tortuous vessels, we performed magnetic resonance tomography (MRT) angiography to look for possible neurovascular anomalies (NVA), which have been previously associated with hypertension. NVA can be caused by a looping posterior inferior cerebellar or vertebral artery. Experimental and clinical evidence suggests that NVA may cause hypertension by a compression of the ventrolateral medulla. METHODS: We performed MRT in 15 hypertensive affected (aged 14 to 57 years) and 12 normotensive nonaffected (aged 12 to 59 years) family members. We then tested for linkage between the hypertension-brachydactyly phenotypes and the presence of NVA. RESULTS: All 15 affected persons had MRT evidence for NVA. All had left-sided posterior inferior cerebellar artery or vertebral artery loops, while 6 had bilateral NVA. None of the nonaffected family members had NVA. The phenotypes were linked with an LOD score of 9.2 given a penetrance of 99%. CONCLUSIONS: Autosomal dominant hypertension and brachydactyly regularly feature NVA, which is frequently bilateral. The early age at which NVA was identified suggests that the condition is primary. We suggest that NVA may be involved in the pathogenesis of this form of hypertension and perhaps essential hypertension as well. Further studies are necessary to address the question of causation.

Abnormalities, Multiple↗
PubMed1997

Endothelial function. General considerations.

The endothelium is involved in both the physiological regulation of vascular tone and the structural transformation of the vessel under pathological conditions. Under physiological conditions, endothelial cells continuously secrete nitric oxide (NO), which relaxes smooth muscle cells and ensures vessel patency. Damaged or excessively activated endothelial cells can also secrete vasoconstrictor factors, the best known of which is endothelin-1 (ET-1), as well as factors that affect the differentiation and growth of vascular smooth muscle cells. How endothelial cell damage contributes, under pathological conditions, to vascular disease can best be illustrated in patients with diabetes mellitus, in whom there are pronounced changes in endothelial cell structure and function. Endothelial cells also interact with cells in the bloodstream, ET-1 and other factors are released from endothelial cells into the bloodstream, where their chemotactic action can induce leucocytes and platelets to migrate to the endothelial wall. Endothelial cells induce adhesion by expression of specific surface adhesion molecules (selectins, integrins and a supergene family of immunoglobulins) that can interact with ligands on the leucocytes and platelets. The expression of adhesion molecules is increased in endothelial cells chronically damaged by risk factors for atherosclerosis. The disturbed permeability of the endothelial layer in patients with diabetes mellitus and/or hyperlipidaemia leads to an increased influx of substances from the circulation into the vessel wall. In addition, endothelial cell dysfunction can lead to accelerated intravessel blood coagulation. It is evident that the endothelium plays a central role in many of the early pathophysiological processes involved in atherosclerosis. It is therefore important to investigate the effects of antiatherosclerotic therapy on endothelial cell function and cell-to-cell interactions. Until recently, little was known about the direct effects of calcium antagonists on endothelial cell function. Recent studies, including two clinical studies, indicate that calcium antagonists primarily affect interactions of endothelial cells, smooth muscle cells, monocytes and platelets, which play a central role in the early phases of the development of atherosclerosis, whereas the protective effect of these agents on the vascular system appears to be low at later stages.

Animals↗
PubMed1997

Effect of water and bicarbonate loading in patients with chronic renal failure.

Animal studies suggest that alkalinization and increased intake of free water both serve to decrease the rate of progression in chronic renal failure. However, clinicians have been reluctant to apply either strategy because of concerns regarding volume overload and water intoxication. We tested the effects of 2 1 daily water supplementation, with either an electrolyte-poor or a HCO3-rich (47.5 mmol/1) water in 11 patients with chronic renal failure (creatinine clearance 10 +/- 5 ml/min). The patients were brought into balance on a diet containing 80 mmol/24 h Na+, 80 mmol/24 h Cl- and 70 mmol/24 h K+. After a 3-day equilibration period, the patients were randomized to one or the other regimen for 7 days. After a 3-day washout period, the alternate regimen was given for another 7 days. Neither regimen led to weight gain or hyponatremia. The supplemental 95 mmol/24 h HCO3- lowered the serum Cl- concentration and raised the serum HCO3- concentration, as well as the pH value, to normal. Creatinine clearance and protein excretion were not affected. Serum beta 2-microglobulin concentrations decreased with the NaHCO3-containing water. Na+/H(+)-antiporter activity was not consistently influenced since an order effect of the regimens was apparent. We conclude that 2 1/24 h water and NaHCO3 supplementation is well tolerated, causes no deleterious effects, and may evoke improvement in patients with chronic renal failure.

Acid-Base Equilibrium↗
PubMed1996

Signaling effects of alpha-thrombin and SFLLRN in rat glioma C6 cells.

Effects of thrombin on brain cells, including change of neurite outgrowth and astrocyte shape, are described, but the molecular mechanisms are unclear. We investigated the effects of human alpha-thrombin and a six amino acid thrombin receptor activating peptide (TRAP-6, SFLLRN) on [Ca2+]i, phosphoinositide hydrolysis, and protein kinase C in rat glioma C6 cells. Stimulation of C6 cells with both alpha-thrombin and TRAP-6 resulted in [Ca2+]i mobilization, [3H]Inositol phosphate response, and enhanced immunoreactivity of the protein kinase C (PKC) isoenzymes alpha, beta, gamma, delta, and epsilon. Results suggest that alpha-thrombin and TRAP-6 activate at least partially the same intracellular signaling pathways in rat glioma C6 cells, which is evidence for involvement of "tethered ligand" receptor in thrombin induced signaling in glioma C6 cells.

Animals↗
PubMed1996

Protein kinase C bound to the Golgi apparatus supports the formation of constitutive transport vesicles.

Constitutive secretion of heparan sulphate proteoglycans (HSPGs) was stimulated in human hepatoma HepG2 cells by phorbol 12-myristate 13-acetate (PMA) and inhibited by calphostin C, a specific inhibitor of protein kinase C (PKC). To delineate more closely the site of PKC action, the packaging in vitro of 35SO4-labelled HSPGs into transport vesicles was investigated. Formation of transport vesicles at the trans-Golgi network was stimulated by PMA and inhibited by calphostin C or Ro 31-8220 by using a post-nuclear supernatant. Treatment of either isolated Golgi-enriched membranes or cytosolic proteins with calphostin C provided evidence that membrane-bound PKC forms strongly supported vesicle formation, whereas cytosolic PKC forms showed a marginal effect. The PKC isoforms PKC-alpha and PKC-zeta were attached to highly purified Golgi membranes, as shown by Western blotting. Both isoforms were localized by confocal immunofluorescence microscopy in the Golgi area of HepG2 cells. Immunoelectron microscopy of ultrathin cryosections of HepG2 cells showed that PKC-zeta predominantly attaches to the trans-Golgi region, whereas PKC-alpha binds to the cis- and trans-Golgi area.

Carcinoma, Hepatocellular↗
PubMed1996

Anti-endothelial cell antibodies in Takayasu arteritis.

BACKGROUND: Although a specific etiology for Takayasu arteritis has not been found, the bulk of evidence favors an autoimmune mechanism. We examined the sera of 19 patients with Takayasu arteritis for antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-DNA antibodies, antibodies to extractable nuclear antigens (ENA), anti-Ro anti-bodies, anticardiolipin antibodies, circulating immune complexes, and anti-endothelial cell antibodies (AECA). METHODS AND RESULTS: We used enzyme-linked immunoassays, immunofluorescence, counterimmunoelectrophoresis, fluorescent-activated cell sorter (FACS) analysis, and confocal microscopy. We found that although no patient had positive ANCA, ANA, anti-DNA antibodies, ENA antibodies, anti-Ro antibodies, or anticardiolipin antibodies, 18 of the 19 patients had AECA. The AECA titers of the patients were 2561 +/- 1458 compared with 126 +/- 15 arbitrary units in a normal group of control subjects (P < .001). To verify the specificity of AECA, we performed cytofluorimetry on human endothelial cells with the sera from patients and control subjects. Two entirely separate patterns of fluorescence intensity were identified. We next performed immunocytochemistry and confocal microscopy with human endothelial cells subjected to patients' sera and to sera from normal subjects. The cells subjected to sera from patients with Takayasu arteritis demonstrated specific immunofluorescent staining of their plasma membrane and cytosol. CONCLUSIONS: AECA are frequently present in patients with Takayasu arteritis. They may play a role in the pathogenesis. Furthermore, they may be useful as an additional diagnostic tool.

Adolescent↗
PubMed1996

Transvaginal sonography and hysteroscopy in women with postmenopausal bleeding.

OBJECTIVE: To make a prospective comparison between endometrial thickness determined by transvaginal sonography (TVS) and hysteroscopic findings in women with postmenopausal bleeding with histologic findings obtained by dilatation and curettage (D&C). METHODS: Eighty-one patients who had not received hormonal replacement therapy were scanned by transvaginal probe, and double-layer endometrial thickness was measured 1 day before hysterectomy and D&C. RESULTS: The histologic diagnosis was atrophy in 12 cases, irregular proliferative changes in 21, endometrial polyps in 16 hyperplasia in 16 and endometrial carcinoma in 16. TVS detected 46 of 48 pathologic conditions, including all cases of endometrial carcinoma if the endometrial thickness (both layers) was > or = 5 mm (sensitivity 95.8%, specificity 4.5%). Hysteroscopy also detected the endometrial pathology in 46 of 48 cases but with a higher specificity (sensitivity 95.3%, specificity 93.9%). CONCLUSION: TVS and hysteroscopy are complementary diagnostic methods and could be accurately used to discriminate normal and pathologic conditions in patients with postmenopausal bleeding.

Aged↗
PubMed1996

Expression of membrane form of the pregnancy associated protein TJ6 on decidual lymphocytes in the first trimester of pregnancy.

TJ6, a newly described protein produced locally in the uterine decidua during pregnancy, may be involved in maintaining a unique immunological environment at the maternal-fetal interface. The aim of this study was to determine whether TJ6 is expressed as membrane form on decidual lymphocytes (DL), to define the phenotypes of TJ6m (membrane form TJ6) expressing cells and to analyze the fluorescence intensity of TJ6m expression. Peripheral blood lymphocytes (PBL) and DL were obtained from first trimester pregnancies undergoing elective termination and immunophenotyped for TJ6m and other cell surface antigens (CD3, CD8, CD19, CD56, CD16) by flow cytometry. This is the first study showing that TJ6 molecules are present on decidual lymphocytes in human pregnancy. TJ6m expression on PBL was not different from that of DL. However, a significantly higher percentage of double positive (TJ6m+CD3+, TJ6m+,CD8+,TJ6m+CD19+) cells were found in PBL when compared to DL. The average fluorescence intensity (AFI) for the TJ6m marker among cells with CD8+, CD19+ and CD56+ double positive was significantly higher in DL as compared with those of PBL. The AFI for granularity of double positive DL was significantly higher than observed in PBL.

Antigens, CD↗
PubMed1996

Disease activity and autoantibodies to endothelial cells in patients with Wegener's granulomatosis.

The purpose of this study was to assess the utility of antiendothelial cell antibodies (AECAs) in patients with active and inactive Wegener's granulomatosis. We studied 32 patients with Wegener's disease (clinical criteria and biopsy, as well as titers of antineutrophil cytoplasmic antibodies with a cytoplasmic pattern [cANCA]) over 4 years and compared their AECA values with those of 24 normal subjects similar in age and gender distribution, as well as with those of patients with chronic glomerulonephritis with or without dialysis and of patients with severe arteriosclerosis. We measured AECAs, cANCAs, C-reactive protein, erythrocyte sedimentation rate, proteinuria, and renal function in patients with active disease or in patients reactivating their disease. A time course with repeated AECAs was conducted over 27 months in 24 patients. The AECAs were measured with an enzyme-linked immunosorbent assay. The specificity was verified with immunofluorescent confocal microscopy, which showed the AECA epitopes to be within the cytoplasm of endothelial cells. Elevated AECA titers were found in all patients with active disease, not all of whom had positive cANCAs. Although elevated AECAs were also found in some patients with inactive disease, normal AECA values were seen only in patients with inactive disease. Patients with active disease entering remission showed a decrease in AECA titers, while patients entering a relapse increased their AECA titers. We conclude that AECAs are present in patients with Wegener's granulomatosis. To our knowledge, these are the first serial AECA observations. Our data suggest that AECAs are correlated with disease activity. Antiendothelial cell antibody values in the normal range strongly support remission. These findings may be of clinical utility in distinguishing relapse from concomitant illness.

Autoantibodies↗
PubMed1996

Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat.

The leukocyte adhesion molecule ICAM-1 is implicated in ischemic renal reperfusion injury. We tested the utility of an ICAM-1 antisense oligodeoxyribonucleotide (ODN) with lipofectin, six hours prior to 30 minutes of bilateral renal ischemia in the rat. We measured ICAM-1 expression by immunohistochemistry and Western blot. Our antisense ODN showed a specific ICAM-1 surface expression inhibition in vitro. We then assessed ICAM-1 expression, leukocyte infiltration, serum creatinine, serum urea concentration, and renal histology in rats subjected to renal ischemia and controls. Serum creatinine and urea concentrations 12 and 24 hours post-ischemia were increased in saline treated and reverse ODN treated rats, compared to antisense ODN treated or sham operated rats (P < 0.05). Western blotting showed decreased ICAM-1 protein in antisense ODN-treated kidneys, compared to reverse ODN treated and saline treated ischemic controls (P < 0.05). Antisense ODN also ameliorated the ischemia-induced infiltration of granulocytes and macrophages (P < 0.05), and resulted in less cortical renal damage as assessed by a quantitative pathological grading scale (P < 0.05), compared to reverse ODN or saline treatment. Thus, antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. The clinical applicability of these findings extends beyond ischemic acute renal failure.

Acute Kidney Injury↗
PubMed1996

Signal transduction of erythropoietin in endothelial cells.

Erythropoietin (EPO) induces endothelin expression in endothelial cells (EC) and has angiogenic effects. We investigated the intracellular signal transduction of EPO in EC and tested the hypothesis that the proliferative effects of EPO may be mediated by cytosolic calcium, changes in intracellular pH, or tyrosine phosphorylation. Cytosolic calcium and pH were measured with fura-2 and BCECF. Protein phosphorylation was assessed with 32P-labeled EC and two-dimensional (2D) gel chromatography. Tyrosine phosphorylation was measured using specific antityrosine antibodies and confocal microscopy. Proliferation was measured by thymidine incorporation and cell count. No effects of EPO on cytosolic calcium and pH were observed. In contrast, erythropoietin increased phosphorylation of 94, 70, 42, 40, 29 and 25 kDa proteins at five minutes and 60 minutes. Most of the early proteins were tyrosine phosphorylated. Confocal microscopy showed cytosolic as well as membrane-bound tyrosine phosphorylation in resting cells and an EPO-induced translocation of immunoreactivity to the nucleus. Immunostaining for the transcription factor STAT-5 showed that EPO induced a nuclear translocation of STAT-5. EPO 0.5, 2, and 4 U/ml increased proliferation, an effect that was prevented by incubation with the tyrosine kinase inhibitor genistein. We conclude that EPO induces proliferation in EC initially via tyrosine phosphorylation of six distinct proteins, and that the phosphorylation and nuclear translocation of the transcription factor STAT-5 is important for the effects of EPO on EC.

Biological Transport, Active↗
PubMed1996

Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12.

Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

Adult↗