Effect of Pioglitazone on Endoplasmic Reticulum Stress and Autophagy Response in the Perivascular Adipose Tissue of Type 2 Diabetic Rats.

Abstract

Perivascular adipose tissue (PVAT) plays a crucial role in vascular homeostasis. Recent studies in adipose tissue demonstrated that endoplasmic reticulum (ER) stress and autophagy are activated in Type 2 diabetes mellitus (T2DM), while the precise role of ER stress and autophagy in PVAT is unclear. We aimed to investigate the possible influence of pioglitazone on ER stress and autophagy response in PVAT of T2DM rats. T2DM was induced by high-fat diet/low-dose streptozotocin (HFD/STZ) in male Wistar rats (8-10 weeks), and pioglitazone (20 mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters (nonfasting glucose, total cholesterol, and triglyceride) were verified in blood samples. ER stress-related (ATF4, CHOP, and GRP78) and autophagy-related (MAP1LC3B/LC3-II, BECN-1/Beclin, and SQSTM1/p62) gene expression levels in thoracic PVAT were measured by RT-PCR. Pioglitazone treatment reversed the increased nonfasting glucose and triglyceride levels in T2DM. ER stress and autophagy responses were significantly increased in PVAT of T2DM rats. Pioglitazone increased ER stress-related GRP78 gene expression while decreasing autophagy-related MAP1LC3B and BECN-1 gene expression levels in T2DM. Interestingly, SQSTM1 gene expression levels were increased by pioglitazone in the control and T2DM groups. The current study provides original findings regarding the effects of pioglitazone on ER stress and autophagy response in PVAT of HFD/STZ-induced T2DM rats. Pioglitazone treatment in T2DM increased GRP78 and SQSTM1 gene expressions, which both play a crucial role in adipocyte differentiation and adipogenesis, besides ER stress and autophagy. Further studies clarifying the adipogenic effect of pioglitazone on PVAT are needed for a better understanding of its effect on the vascular system.