Endoplasmic Reticulum Stress in the Development of Endothelial Dysfunction and Kidney Disease

Persistent hyperglycemia in type I diabetes triggers numerous signaling pathways which leads to different complications such as diabetic kidney disease (DKD), endothelial dysfunction, retinopathy etc. Diabetes and associated complications are diseases of multiple etiology and difficult to control targeting a single pathway. This study was conceived to evaluate the potential of two different combinations using ER stress inhibitor in combination with angiotensin converting enzyme 2 (ACE2) activator and angiotensin TT type I receptor blocker (A Tl R blocker) against two different complications of diabetes, endothelial function and DKD respectively. This study also delves into the understanding the regulation of ER stress during the development of DKD using epigenetic tools.

Since, hyperglycemia damages endothelial layer via multiple signaling pathways including enhanced oxidative stress, downregulation of angiotensin converting enzyme 2 signaling and exacerbation of endoplasmic reticulum stress etc., hence it becomes difficult to prevent the injury using monotherapy. Thus, present study was aimed to evaluate the combined effect of endoplasmic reticulum stress inhibition along with angiotensin converting enzyme-2 activation, two major contributors to hyperglycemia induced endothelial dysfunction, in preventing endothelial dysfunction associated with type I diabetes. Streptozotocin induced diabetic animals were treated with either diminazene aceturate (5 mg kg-day-1, p.a.) or tauroursodeoxycholic acid, sodium salt (200 mg kg- day-1 i.p.) or both for four weeks. Endothelial dysfunction was evaluated using vasoreactivity assay where acetylcholine induced relaxation was assessed in phenylephrine precontracted rings. Combination therapy significantly improved the vascular relaxation when compared to diabetic control as well as monotherapy. Restoration of nitrite levels along with prevention of collagen led to improved vasodilatation. Moreover, there was an overall reduction in aortic oxidative stress.