The Mechanisms Of Aldosterone Induced Pancreatic β-cell Failure In Diabetes

Diabetes is a metabolic disease caused by absolute or relative inadequancy of insulin and characterized by chronic hyperglycemia. Pancreatic β-cells dysfunction is the common character of type1and type2diabetes. The activation of RAAS cause a increasing level of aldosterone, which closely related to diabetes. The aim of this study was to investigate the effect of aldosterone on the function and survival of pancreatic beta cells and to explore the molecular mechanisms involved in the aldosterone-induced impairment of pancreatic beta cells.We have found that aldosterone impaired beta-cell lines (Min6cells and INS-1cells) and islet by causing a decrease of insulin synthesis and secretion and an increasing apoptosis in a dose-dependent manner. Our study have reported for the first time that aldosterone inducing impairment of pancreatic beta cells was found to be independent on MR but dependent on GR. The impairment of aldosterone on pancreatic beta cells could be restored by GR antagonist RU486or GR (NR3C1) knockdown. The molecular mechanism study showed that the treatment of aldosterone caused a decreasing protein level and transcriptional activity of MafA by GR. Moreover, aldosterone induced JNK and P38MAPK activation in beta cells involves a GR-dependent pathway. We have also found that aldosterone regulated the protein levels of MafA at the transcriptional or post-transcriptional level through JNK and p38activation, respectively. Furthermore, overexpression of MafA in Min6and INS-1cells could reverse aldosterone-induced impairment of insulin secretion and synthesis. Besides, overexpression of MafA protected beta cells from aldosterone-induced apoptosis under which the mechanism is involved in a significant decrease of Bcl-2expression.In conclusion, our research has demonstrated that aldosterone induces pancreatic β-cells dysfunction and apoptosis. And the mechanism is that aldosterone inhibites protein level and transcriptional activity of MafA through GR-JNK/p38MAPK pathway. Our findings contribute to the understanding of the relationship between type2diabetes mellitus and the diseases, including hypertention, which relate to the activation of RAAS. And Our study provides experimental and theoretical basis for treating type2diabetes mellitus with Angiotensin receptor blockers such as losartan.