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  • 1
    ISSN: 1432-0428
    Schlagwort(e): Nicotinamide ; streptozotocin ; albumin permeation ; glomerular filtration rate ; blood flow ; urinary protein excretion
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Rats injected i. p. with a single dose of nicotinamide (250 mg/kg) 15 min prior to i.v. injection of streptozotocin (65 mg/kg) develop a very mild form of diabetes characterized by slight elevations of plasma glucose, increased levels of HbA1, and reduced insulin secretion in response to an i.v. glucose tolerance test. These rats gain weight normally and they are not hyperphagic, glycosuric, or polyuric. The effects of this very mild form of diabetes vs overt streptozotocin diabetes of three months duration on regional vascular 131I-albumin clearance, blood flow (assessed by 15 μm 85Sr-microspheres), and renal filtration function were examined in male Sprague-Dawley rats. Plasma glucose levels of rats with mild diabetes were 7.4±0.9 (mean±SD) (mmol/l) vs 6.5±0.6 for control rats and 31.3±6.0 for overtly diabetic rats. HbA1 levels were increased 1.4 fold in mildly diabetic and 2.3 fold in overtly diabetic rats. Vascular clearance of 131I-albumin was markedly increased in ocular tissues (anterior uvea, retina, and choroid), sciatic nerve, aorta, new (subcutaneous) granulation tissue, and kidney of both diabetic groups, although increases in overtly diabetic rats exceeded those in the mildly diabetic group (2.2–4.6 times control animals vs 1.6–3.3 times, respectively). Likewise, both overt and very mild diabetes markedly increased glomerular filtration rate (∼1.8 times and 1.2 times control animals, respectively), urinary excretion of endogenous albumin (∼9 times and 4 times) and IgG (∼15 times and 4 times), as well as regional blood flow in the anterior uvea, choroid, and sciatic nerve. Increases in tissue sorbitol levels were much larger in overtly diabetic rats (generally 10–20 times control animals) than in mildly diabetic rats (1.5–3 times controls). myo-Inositol levels were significantly decreased only in lens and sciatic nerve of overtly diabetic rats. These observations indicate that even very mild diabetes is associated with vascular functional changes which develop more slowly than in overtly diabetic rats, but are disproportionately large (in view of the minimal increases in glycaemia and tissue polyol levels) compared to those in overtly diabetic rats.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    ISSN: 1432-0428
    Schlagwort(e): Keywords Mesangium ; diabetes mellitus ; protein kinase C ; capacitative Ca2 + influx ; store-operated Ca2 + channels.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In cultured mesangial cells (MC), capacitative Ca2 + influx via store-operated channels (SOC) is potentiated by agents that release Ca2 + from intracellular stores, and inhibited by protein kinase C (PKC). Cells grown under high glucose conditions, as a model of the diabetic microenvironment, display reduced Ca2 + signalling in response to vasoconstrictors, probably due to downregulation by elevated PKC activity. Since SOC might be relevant to this phenomenon, we assessed Ca2 + influx by microfluorometry of fura-2-loaded rat MC cultured for 5 days in normal (5.5 mmol/l, NG) or high glucose (30 mmol/l, HG). The addition of 1–10 mmol/l Ca2 + to NG cells equilibrated in Ca2 + -free media induced an immediate Ca2 + influx with a free cytosolic Ca2 + ([Ca2 + ]i) plateau of 155 ± 50 and 318 ± 114 nmol/l, respectively. Basal influx was reduced to 88 ± 8 and 145 ± 17 nmol/l [Ca2 + ]i (1–10 mmol/l Ca2 + , p 〈 0.01) by 30 mmol/l d-glucose. This effect of HG was confirmed by Mn2 + quenching of fura-2, indicating reduced entry of divalent cations via the capacitative pathway. Equimolar l-glucose had no effect on Ca2 + influx, consistent with a non-osmotic mechanism. Arginine vasopressin (10 μmol/l) elicited weaker release of stored Ca2 + and subsequent influx in HG cells (191 ± 33 vs 153 ± 24 nmol/l, 400 ± 76 vs 260 ± 33 nmol/l, 1–10 mmol/l Ca2 + , NG/HG, p 〈 0.05). To examine the involvement of PKC in the effect of HG on capacitative Ca2 + influx, the enzyme was activated or downregulated by treatment with 0.1 μmol/l phorbol myristate acetate (PMA) for 3 min or 24 h, respectively. PMA acutely inhibited Ca2 + influx in NG cells, while PKC downregulation restored it in HG cells. Similarly, the PKC inhibitors staurosporin or H-7 normalized SOC activity in HG cells. In summary, impairment of Ca2 + influx via SOC by HG is one mechanism of the reduced MC [Ca2 + ]i responsiveness to vasoconstrictors. This event is mediated by PKC and may contribute to the glomerular haemodynamic changes in the initial stages of diabetes mellitus. [Diabetologia (1997) 40: 521–527]
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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