An approach to the explanation of cell membrane alteration in primary hypertension.

Postnov, Yu. V.

doi:10.1161/01.hyp.15.3.332

Cited by 35 publications

(11 citation statements)

References 46 publications

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“…Its enhancement in essential hypertension is presumably explained by certain genetic factors [26]. The results of this study show that enhanced NHE in diabetic patients is the earliest sign of susceptibility to nephropathy, when compared to elevated MAP and microalbuminuria.…”

Section: Discussionmentioning

confidence: 53%

Enhanced erythrocyte Na + /H + exchange predicts diabetic nephropathy in patients with IDDM

Koren

Koldanov

Pronin³

et al. 1998

Diabetologia

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Diabetic nephropathy is limited to a subset of patients with long-standing poorly controlled diabetes and an apparent hereditary predisposition [1, 2]. To depict the subset of patients prone to renal damage, several markers, e. g. urinary excretion of very small amounts of albumin (microalbuminuria) [3] and elevation of arterial pressure [4], have been proposed. However, these symptoms appear when the renal damage is already impending [5].Enhanced sodium-lithium countertransport and sodium-hydrogen exchange (NHE) found in blood cells and skin fibroblasts of diabetic patients prone to nephropathy [6±10] represent a very early (if not congenital) sign. Its accuracy in predicting diabetic nephropathy has not been established. In this study we have followed-up non-microalbuminuric patients with IDDM of at least a 10-year duration for 8 years after their first NHE evaluation. Subjects and methodsStudy group. We followed-up 156 patients (98 women, 58 men) aged 33 ± 8 years, with juvenile onset of insulin-dependent diabetes mellitus (diabetes duration prior to enrollment 15 ± 4 years) for 8 years (total diabetes duration 23 ± 3 years). The criteria for the patients' enrollment in the study were: duration of insulin treatment of at least 10 years and up to 25 years, absence of proteinuria/microalbuminuria, normal arterial blood pressure, normal serum urea, creatinine and electrolyte levels, and absence of clinically evident retinopathy at the time of enrollment. Anamnestic or clinical evidence of recurrent or chronic urinary infection was the single exclusion criterion both on enrollment and during the follow-up. Any Diabetologia (1998) Summary Diabetic nephropathy develops in a subset of patients with an apparently hereditary predisposition. Microalbuminuria and elevated arterial pressure have been proposed as predictors of nephropathy but both appear when renal damage is impending. Enhanced sodium-hydrogen exchange in the cell membranes of diabetic patients is an early marker of diabetic nephropathy but its predictive value has not been assessed. In this study, sodium-hydrogen exchange was measured in erythrocytes as an initial velocity of amiloride-inhibited H + efflux (pH 6.35± 6.45) into a Na + -containing medium (pH 7.95±8.05) in 156 non-microalbuminuric insulin-treated diabetic patients (98 women, 58 men, age 33 ± 8 years, diabetes duration prior to enrollment 15 ± 4 years) during 8 years of follow-up. Enhanced erythrocyte sodiumhydrogen exchange predicted diabetic nephropathy alone and in association with a familial tendency to hypertension/nephropathy with 86 and 96 % sensitivity, and 80 % specificity. Thus, sodium-hydrogen exchange appears to detect a subset of diabetic patients prone to develop renal damage, in whom a more intensive treatment modality might be considered.[ Diabetologia (1998) 41: 201±205]

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Section: Discussionmentioning

confidence: 53%

Enhanced erythrocyte Na + /H + exchange predicts diabetic nephropathy in patients with IDDM

Koren

Koldanov

Pronin³

et al. 1998

Diabetologia

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“…NHE enhancement in essential hypertension is generally explained by genetic factors [15,16]. Elevated NHE rates in diabetic patients prone to nephropathy might be mediated by a similar genetic mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Erythrocytes are a good and economic model of the ubiquitous membrane processes. They have the major advantages of lack of genomic and rapid posttranscriptional changes in the ion fluxes, and minimal interference between the external and intracellular membranes because of reduced number of cell compartments [16].…”

Section: Discussionmentioning

confidence: 99%

Amiloride-sensitive Na + /H + exchange in erythrocytes of patients with NIDDM: a prospective study

Koren

Koldanov

Pronin³

et al. 1997

Diabetologia

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Microangiopathy disables thousands of diabetic patients throughout the world. Aggressive treatment modalities, such as combined therapy with antihyperglycaemic drugs and insulin, appear to decrease the extent of microvascular damage, but are associated with increased incidence of hypoglycaemic events and weight gain [1]. Their risk-to-benefit ratio is high also because less than one third of diabetic patients develop nephropathy [2].Attempts have been made to find a marker that can predict micro-angiopathy in diabetes, and identify a group of patients for whom aggressive treatment is indicated despite its possible adverse effects. Urinary excretion of very small amounts of albumin (microalbuminuria) and elevation of arterial pressure [3] have been proposed for this purpose, but both appear when renal damage is already impending [4].Enhanced permeability of extracellular membranes to sodium (defined as sodium-lithium and sodium-hydrogen antiports) found in blood cells and skin fibroblasts of diabetic patients prone to renal damage [5][6][7] is, however, a very early (if not congenital) sign. To assess the reliability of Na + /H + exchange (NHE) study in predicting diabetic nephropathy, we followed initially non-microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM) of at least 10 years' duration for 8 years after NHE evaluation was first made. Diabetologia (1997) Summary Intensive treatment of non-insulin-dependent diabetes mellitus (NIDDM) decreases the rate of microvascular complications, but is associated with increased incidence of cardiovascular morbidity. Enhanced permeability of plasma membranes for sodium (e. g. sodium-hydrogen exchange, NHE) may predict the subset of diabetic patients for whom intensive modalities of treatment are indicated despite their potential risk. However, the accuracy of NHE as a marker of microangiopathy has not been assessed. In this study NHE as initial velocity of amiloride-inhibited H + efflux from erythrocytes (pH i 6.35-6.45) into an Na + -containing medium (pH o 7.95-8.05), was estimated during 8 years of follow-up in 138 non-microalbuminuric diabetic patients (74 women, 64 men, age 52 ± 4 years) treated with antihyperglycaemic drugs for 14 ± 2 years. Appearance of microalbuminuria, overt proteinuria, azotaemia and retinopathy was assessed annually. Enhanced erythrocyte NHE predicted diabetic nephropathy alone and in association with a family history of hypertension and/or nephropathy with a sensitivity of 86 and 93 %, respectively. No association was found between NHE and retinopathy in NIDDM. It is concluded that assessment of erythrocyte NHE can identify a subset of patients likely to develop renal damage, for whom an aggressive treatment approach might be considered. [Diabetologia (1997) 40: 302-306] Keywords Na + /H + exchange, NIDDM, diabetic nephropathy, diabetic retinopathy, erythrocytes.Received: 14 June 1996 and in final revised form: 8 November 1996Corresponding author: W. Koren, M. D., Department of Medicine C, Chaim Sheba Medical ...

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“…sustained PKC activation) could therefore be complemented by inhibition of myosin dephosphorylation as well as the phosphorylation of caldesmon by MAP kinase (45) to provide the overall level of contraction. Studies of genetically transmitted hypertension in rats have identified a polymorphism within the pp60 src locus that is associated with elevated blood pressure (26). This suggests the further possibility that enhanced signaling via the RhoA/PLD pathway could play a role in the elevated vascular resistance that is characteristic of this model of hypertension.…”

Section: Involvement Of Low Molecular Weight G Proteins and Src Inmentioning

confidence: 99%

Reconstitution of α2D-Adrenergic Receptor Coupling to Phospholipase D in a PC12 Cell Lysate

Jinsi-Parimoo

Deth

1997

Journal of Biological Chemistry

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In recent years, efforts to elucidate the biochemical and molecular mechanisms of phospholipase D (PLD) 1 activation have focused interest on both heterotrimeric and Ras-related low molecular weight G proteins (LMWGs) that have been linked to receptor-mediated signal transduction. Evidence for a functional role of G proteins in PLD activation comes from studies in plasma membranes obtained from mammalian cells (1-4) and in cell-free systems prepared from leukocytes (5) and neutrophils (6). A GTP␥S-dependent PLD activity was observed in these preparations only when fractions of both membranes and cytosol were combined. It has been proposed that the cytosol-independent (membrane-dependent) PLD activity represents only a small portion of the total response and that full activation of PLD requires the interplay of cytosolic factors such as PKC, a cytosolic GTP-binding protein, and calcium (7).A number of studies have provided evidence indicating a role for cytosolic LMWGs such as the Rho and Arf families in regulating membrane-associated PLD activity (8 -11). Localization of LMWGs appears to be controlled by their interaction with regulatory proteins such as GTP/GDP dissociation stimulators, GDP dissociation inhibitors, and GTPase-activating proteins (GAPs) (12). Thus reconstitution of receptor-stimulated PLD activity would also be likely to require protein factors from both plasma membrane and cytosolic fractions.Despite the lack of information about the molecular and cellular distinctions between various isoforms of PLD, the actions of its hydrolytic product (phosphatidic acid) have been documented in a broad spectrum of physiologic events and disease states including metabolic regulation, inflammation, secretion, cellular trafficking, diabetes, mitogenesis, oncogenesis, and senescence (13). The exact mechanism by which such diverse short and long term effects are mediated by the activation of PLD is not yet clearly understood. Recently Hammond et al. (14) identified a highly conserved human PLD gene family whose enzyme product is membrane-associated, stimulated by phosphatidylinositol 4,5-bisphosphate, activated by the monomeric G protein ADP-ribosylation factor-1, and inhibited by oleate.The ␣ 2A/D -adrenergic receptor has been demonstrated to transduce a cellular proliferation response mediated through G i proteins (15)(16)(17). It has become evident that this mitogenic signal results from activation of the Ras/mitogen-activated protein (MAP) kinase cascade (18,19), which appears to involve activation by G ␤␥ subunits (20). The intermediate tyrosine kinase pp60src (a member of the src family of tyrosine kinases) has been proposed to phosphorylate Shc, an adapter protein that associates with Grb2-Sos complexes through the SH2 domain of Grb2, thereby leading to Ras activation (21).Given these findings we sought to investigate the involvement of Ras-related proteins in the ␣ 2A/D -adrenergic receptor cellular signaling process. The ␣ 2A/D -adrenergic receptor has been shown to couple to PLD in a tyrosine kinase-...

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An approach to the explanation of cell membrane alteration in primary hypertension.

Cited by 35 publications

References 46 publications

Enhanced erythrocyte Na + /H + exchange predicts diabetic nephropathy in patients with IDDM

Enhanced erythrocyte Na + /H + exchange predicts diabetic nephropathy in patients with IDDM

Amiloride-sensitive Na + /H + exchange in erythrocytes of patients with NIDDM: a prospective study

Reconstitution of α2D-Adrenergic Receptor Coupling to Phospholipase D in a PC12 Cell Lysate

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