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Mogher Khamaisi Allan Flyvbjerg Ziv Haramati Gadi Raz Isaiah D. Wexler Itamar Raz 《Experimental diabetes research》2002,3(4):257-264
The metabolic aberrations associated with diabetes mellitus
profoundly alter the growth hormone/insulin-like growth factor I
(GH/IGF-I) system. In severe experimental diabetes, serum IGF-I
level is reduced, reflecting altered hepatic expression. On the other
hand, increased levels of kidney IGF-I have been implicated in the
development of diabetic kidney disease. This study aimed to examine
the effect of mild experimental diabetes with hypoinsulinemia
on both the systemic and renal GH/IGF-I systems in a low-dose
streptozotocin (STZ)-induced diabetic rat. Diabetic animals with
mild hypoinsulinemia developed renal hyperfiltration within 3 days
of diabetes, whereas the renal size increased significantly only between
30 and 48 days of diabetes. Plasma GHlevels were unchanged
during the entire course of the study, but a decrease in serum
IGF-I, IGF-binding protein 3 (IGFBP-3), and IGF-binding protein
4 (IGFBP-4) occurred after 10, 30, and 48 days. Kidney IGF-I
and IGF-binding protein 1 (IGFBP-1) mRNA expression increased
after 10 and 30 days of diabetes. A significant increase in kidney
IGFBP-1/2, IGFBP-3, and IGFBP-4 proteins was seen after 48 days
of diabetes.Apositive correlations was found between renal growth
and insulin/glucose ratio (r = .57), kidney IGF-I (r = .57), IGFBP-1
mRNA(r = .43), IGFBP-1/2 (r = .41), and IGFBP-4 levels (r = .40).
These results demonstrate hyperfiltration within 3 days of diabetes
and a similar response in the IGF-I system in mildly and severely hypoinsulinemic
rats; however, renomegaly develops slower in mildly diabetic rats at least partly due to delayed changes in the renal IGF
and IGF BPs. 相似文献
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Niroz Abu-Saleh Hiba Yaseen Safa Kinaneh Mogher Khamaisi Zaid Abassi 《Journal of cellular and molecular medicine》2021,25(4):1884-1895
Endothelial dysfunction (ED) is a key feature of diabetes and is a major cause of diabetic vasculopathy. Diabetic patients who also exhibit hyperlipidaemia suffer from accelerated vascular complications. While the deleterious effects of high glucose levels (HG) and hyperlipidaemia alone on ED are well established, the effects of combined hyperlipidaemia and HG have not been thoroughly studied. Therefore, the current study examines whether HG and hyperlipidaemia exert synergistic ED, and explores the mechanisms underlying this phenomenon. We applied multi-disciplinary approaches including cultured HUVECs and HMEC-1 as well as knockout mice CByJ.129S7(B6)-Ldlrtm1Her/J (LDLR−/−) to investigate the mechanisms underlying combined HG and hyperlipidaemia-induced ED. Incremental doses of glucose in the presence or absence of OxLDL were added to HUVECs and HMEC-1. After 5 days, the status of nitric oxide (NO) and endothelin (ET)-1 systems as well as their signal transduction were assessed using Western blot, ELISA and immunoreactive staining. The effects of chronic combination of HG and hyperlipidaemia on endothelial integrity and function as well as alterations in circulatory NO and ET-1 systems were examined in knockout mice LDLR−/− and their wild-type. HUVEC cells exposed to HG and OxLDL displayed enhanced ET-1 production, more than HG or OxLDL when added alone. Overproduction of ET-1 stems from up-regulation of endothelin converting enzyme (ECE)-1 as observed under these conditions. In contrast, combination of HG and OxLDL dramatically decreased both total endothelial NO synthase (eNOS) by 60%, and activated eNOS (peNOS) by 80%. Moreover, NRF2 decreased by 42% and its active form (pNRF2) by 56%, as compared to baseline. Likewise, ETB levels decreased by 64% from baseline on endothelial cells. Furthermore, diabetic LDLR−/− mice displayed a higher blood pressure, plasma triglycerides, cholesterol, ET-1 and NO2/NO3 levels, when compared with normoglycemic LDLR−/− and BALB mice. Combined hyperglycaemia and hyperlipidaemia activates the ET system and attenuates the nitric oxide system with the Nrf2 signalling pathway. These findings suggest that perturbations in these paracrine systems may contribute to ED. 相似文献
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