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  • 1
    Electronic Resource
    Electronic Resource
    Enhanced G protein activation in IDDM patients with diabetic nephropathy (1998)
    Springer
    Diabetologia 41 (1998), S. 94-100 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin-dependent diabetes mellitus ; diabetic nephropathy ; G protein activation ; cellular signalling ; lymphoblasts ; platelet-activating factor.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Genetic susceptibility contributes significantly to the risk of developing nephropathy in insulin-dependent diabetes mellitus (IDDM). The cellular substrate for this has remained enigmatic. We investigated whether afflicted IDDM patients display an enhanced activation of pertussis toxin (PTX)-sensitive G proteins, a phenomenon which has been demonstrated in patients with essential hypertension. We established immortalised B lymphoblast cell lines from 10 IDDM patients without nephropathy (DC) and 15 IDDM patients with nephropathy (DN). Nephropathy was defined as a persistent albumin excretion rate of more than 20 μg/min (DC 3.9 ± 5.8, DN 562.3 ± 539.0 μg/min, respectively). Subjects were matched with regard to age (DC 28.9 ± 6.5, DN 35.9 ± 9.9 years), diabetes duration (DC 19.3 ± 6.9, DN 22.7 ± 5.8 years) and HbA1 c values (DC 8.5 ± 1.4, DN 8.8 ± 1.6 %). Reactivity of PTX-sensitive G proteins was quantified by measuring platelet-activating factor (PAF)-induced Ca2 + mobilisation (fura 2 method) and by mastoparan-stimulated [35S]GTPγS binding. Expression of Gαi proteins was quantified by Western blot analysis. PAF-evoked Ca2 + increases above baseline averaged 77.0 ± 52.5 nmol/l in DC and 150.7 ± 61.5 nmol/l in DN (p = 0.005). PAF-evoked Ca2 + increases correlated with stimulated [35S]GTPγS binding (r 2 = 0.42, p = 0.012). From Western blot analysis an overexpression of Gαi proteins could be excluded in DN. A consequence of the altered metabolic milieu in diabetes is the increased release of vasoactive and proliferative agonists which promote glomerular hyperfiltration, hypertrophy, enhanced matrix deposition, and, finally, glomerulosclerosis. Many of these auto- and paracrine agonists bind to G protein-coupled receptors. Therefore, their cellular effects are reinforced by the enhanced G protein reactivity and increase the propensity to nephropathy in IDDM. [Diabetologia (1998) 41: 94–100]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050872
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    The G protein β3 subunit splice variant Gβ3-s causes enhanced chemotaxis of human neutrophils in response to interleukin-8 (1999)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 360 (1999), S. 27-32 
    Details
    ISSN: 1432-1912
    Keywords: Key words Calcium ; Leukocytes ; Signal transduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A C825T polymorphism was recently described in GNB3, the gene encoding the Gβ3 subunit of heterotrimeric G proteins. The 825T allele is associated with the expression of a shorter splice variant (Gβ3-s) and enhanced signal transduction via pertussis toxin (PTX)-sensitive G proteins. Given the pivotal role of G protein βγ dimers in chemotaxis, we related the genotype at the GNB3 locus as a marker for Gβ3-s expression to chemotaxis of human neutrophils in response to stimulation with interleukin-8 (IL-8). IL-8, which activates a CXC receptor coupled to PTX-sensitive G proteins, induced at 10 nM an enhanced maximum chemotaxis of neutrophils from individuals with TC/TT genotype compared to CC genotype. Furthermore, migration of neutrophils from 825T allele carriers was 2.5-fold higher at 0.1 nM and 1 nM IL-8. At these concentrations of IL-8, no significant chemotaxis was observed in neutrophils from homozygous C825 allele carriers, indicating a genotype-dependent, different potency of IL-8 to chemoattract neutrophils. In contrast, IL-8-induced Ca2+ signals and O2– generation were independent of genotype. The role of Gβ3-s in enhanced chemotaxis could be confirmed by determination of chemotaxis of COS-7 cells following transfection with either Gβ3-s or "wild-type" Gβ3. Upon stimulation of the transfected cells with the chemoattractant lysophosphatidic acid (LPA), we observed an enhanced chemotactic response of Gβ3-s-transfected compared to Gβ3-transfected COS-7 cells, confirming that Gβ3-s actually causes enhanced chemotaxis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002109900040
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Na+/H+ exchange in hypertension and in diabetes mellitus—facts and hypotheses (1996)
    Springer
    Basic research in cardiology 91 (1996), S. 179-190 
    Details
    ISSN: 1435-1803
    Keywords: Hypertension ; diabetes ; nephropathy ; G proteins ; hypertrophy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An enhancement of Na+/H+ exchange (NHE) in blood cells of selected patients with essential hypertension and with diabetic nephropathy has been described by various investigators. Recent studies have shown that enhanced NHE activity persists in immortalized lymphoblasts from these patients after prolonged cell culture and, thus, appears to be under genetic control. Available evidence strongly argues against a mutation in the encoding gene or an overexpression of the NHE. Immortalized cells from hypertensive patients with enhanced NHE activity display two-fold enhanced agonistinduced rises of the cytosolic free Ca2+ concentration and the underlying reason was identified as an increased activation of pertussis toxin (PTX)-sensitive G proteins. The molecular mechanism(s) of this phenomenon have not yet been elucidated. It appears likely that similar changes contribute to the enhanced NHE activity phenotype in diabetic nephropathy, although experimental evidence for this is still lacking. An enhanced activation of PTX-sensitive G proteins could explain many of the hitherto unexplained phenomena in essential hypertension, e. g. inheritance, increased vasoconstriction, hypertrophy or remodeling of arterial blood vessels and the heart, enhanced platelet aggregation etc. In diabetes the same defect could provide the basis for the susceptibility to nephropathy, e.g. by enhancing the deleterious effects of autocrine and paracrine growth, factors. Thus, the experimental approach of immortalizing blood cells from patients with essential hypertension and diabetic nephropathy has opened new horizons in the identification of genetically fixed abnomalities in intracellular signal transduction which could contribute to both pathologies and which can now be studied without the confounding influences of the diabetic or hypertensivein vivo milieu.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00788904
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    Paper (German National Licenses)
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