ABSTRACT
The prevalence of obesity, metabolic syndrome and diabetes has been increasing rapidly worldwide. These are a group of metabolic disorders characterized by a chronic hyperglycaemic condition resulting from defects in insulin secretion, insulin action or both. The control of body weight and blood glucose concentrations depends on the exquisite coordination of the function of several cells, organs and tissues. Underlying mechanisms of obesity and insulin resistance remain uncertain. Adipose tissue is composed of heterogeneous cell types. Immune cells within adipose tissue also likely contribute to systemic metabolic processes. Increased production of local and systemic adipokines and cytokines, polarization of macrophages, T helper subtype changes could contribute to pathologies linking obesity to diabetes, both by decreasing insulin sensitivity, by compromising β-cell function and disturbing adipose tissue metabolism and distribution. Tissue oxygen (O2) levels, hypoxia inducible factor (s) (HIFs) secretion differences regulate the plasticity of macrophages and the polarization of macrophages controls functionally divergent processes in cells. A hypoxic and inflammatory phenotype has been reported in adipose tissue during obesity. Therefore, the present review focuses HIFs-mediated effects of hypoxia in adipocyte inflammation and macrophage polarization associated with obesity pathogenesis.
ABSTRACT
Background & objectives: Erythropoietin (EPO) has cytoprotective and anti-apoptotic effects in pathological conditions, including hypoxia and ischaemia-reperfusion injury. One of the targets to protect against injury is ATP-dependent potassium (KATP ) channels. These channels could be involved in EPO induced ischaemic preconditoning like a protective effect. We evaluated the cell cytoprotective effects of EPO in relation to KATP channel activation in the renal tubular cell culture model under hypoxic/normoxic conditions. Methods: Dose and time dependent effects of EPO, KATP channel blocker glibenclamide and KATP channel opener diazoxide on cellular proliferation were evaluated by colorimetric assay MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] under normoxic and hypoxic conditions in human renal proximal tubular cell line (CRL-2830). Evaluation of the dose and time dependent effects of EPO, glibenclamide and diazoxide on apoptosis was done by caspase-3 activity levels. Hypoxia inducible factor-1 alpha (HIF-1 α) mRNA levels were measured by semi-quantative reverse transcription polymerase chain reaction (RT)-PCR. Kir 6.1 protein expresion was evalutaed by western blot. Results: Glibenclamide treatment decreased the number of living cells in a time and dose dependent manner, whereas EPO and diazoxide treatments increased. Glibenclamide (100 μM) treatment significantly blocked the anti-apoptotic effects of EPO (10 IU/ml) under both normoxic and hypoxic conditions. EPO (10 IU/ml) and diazoxide (100 μM) treatments significantly increased (p<0.01) whereas glibenclamide decreased (p<0.05) HIF-1 α mRNA expression. Glibenclamide significantly (p<0.01) decreased EPO induced HIF-1 α mRNA expression when compared with the EPO alone group. Interpretation & conclusions: Our results showed that the cell proliferative, cytoprotective and anti-apoptotic effects of EPO were associated with KATP channels in the renal tubular cell culture model under hypoxic/normal conditions.