Mark Cukiernik

Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy

Several interactive and mutually perpetuating abnormal biochemical pathways, such as protein kinase C (PKC) activation, augmented polyol pathway, and non‐enzymatic glycation, may be activated as a result of sustained hyperglycemia in diabetes. These abnormal pathways may in turn influence several vasoactive factors, which are probably instrumental in the production of functional and morphological changes in the retina in diabetes. The vasoactive factors such as endothelins, nitric oxide, vascular endothelial growth factors, etc., are of importance in mediating functional and structural alterations in early diabetic retinopathy. Intricate and interactive regulatory mechanism(s) among these factors may control ultimate availability of these molecules to produce biologically significant effects. A better understanding of these factors and their interactions would aid the development of adjuvant therapies for the treatment of diabetic retinopathy. Copyright

Hyperhexosemia Induced Functional and Structural Changes in the Kidneys: Role of Endothelins

Background/Aims: Glomerular basement membrane (GBM) thickening and mesangial matrix expansion are characteristic features of diabetic nephropathy. The present study investigates the role of endothelins (ETs) in the pathogenesis of such changes in diabetic nephropathy. Methods: Diabetic (streptozotocin-induced, 65 mg/kg), galactose-fed (30%) and control animals were followed up for 1 and 6 months. Animal groups also included diabetic and galactose fed animals on dual ETA/ETB receptor antagonist bosentan (100 mg/kg). A semi-quantitative reverse transcription polymerase chain reaction method was used to quantify mRNA expression of ET-1, ET-3, ETA, ETB, fibronectin and collagen α2(IV). Histological analyses of the kidneys and ET-1, ET-3 and fibronectin immunohistochemistry were performed. Morphometric assessment of the GBM after 6 months was performed. Results: Diabetes increased mRNA expression of ET-1, ET-3, ETA, ETB, fibronectin and collagen α2(IV) after one and six months. In contrast, although increased ETA and ETB mRNAs were present following galactose feeding both at 1 and 6 months, ET-1, ET-3, fibronectin and collagen α2(IV)mRNAs were increased after 6 months. Both diabetes and galactose feeding caused increased GBM thickening. Furthermore, diabetes caused an increase in mesangial matrix production. Bosentan prevented increased fibronectin and collagen α2(IV) mRNA expression, increased mesangial matrix deposition and GBM thickening. Conclusion: This study has demonstrated that diabetes and galactose feeding induced functional and structural changes in the kidney are mediated via ETs.

Contributions of endothelin-1 and sodium hydrogen exchanger-1 in the diabetic myocardium.

Endothelin‐1 (ET‐1) and sodium hydrogen exchanger‐1 (NHE‐1) are important mediators of several disease processes affecting the heart, especially relating to myocardial ischemia. There is evidence that their actions may be interrelated. Their contributions to diabetic heart disease have not been extensively documented. Accordingly, the aim of this study was to investigate the interactive roles of ET‐1 and NHE‐1 in the pathogenesis of diabetic cardiomyopathy, a significant cause of morbidity in diabetic patients.

Alteration of endothelins: a common pathogenetic mechanism in chronic diabetic complications.

Endothelin (ET) peptides perform several physiological, vascular, and nonvascular functions and are widely distributed in a number of tissues. They are altered in several disease processes including diabetes. Alteration of ETs have been demonstrated in organs of chronic diabetic complications in both experimental and clinical studies. The majority of the effects of ET alteration in diabetes are due to altered vascular function. Furthermore, ET antagonists have been shown to prevent structural and functional changes induced by diabetes in animal models. This review discusses the contribution of ETs in the pathogenesis and the potential role of ET antagonism in the treatment of chronic diabetic complications.

Therapeutic potential of endothelin receptor antagonists in diabetes

Endothelins (ETs) are widely distributed in the body and perform several vascular and non-vascular functions. Experimental evidence indicates that abnormalities of the ET system occur in several organs affected in chronic diabetic complications. Furthermore, ET antagonists were found to prevent structural and functional changes in the target organs of chronic diabetic complications in animal models. Abnormalities of plasma ET levels have also been demonstrated in human diabetes. This review discusses the role of ET in the pathogenesis of chronic diabetic complications. The current experimental evidence suggests that ET antagonism may potentially represent an adjuvant therapeutic tool in the treatment of chronic diabetic complications.

The role of the sodium hydrogen exchanger-1 in mediating diabetes-induced changes in the retina

The sodium hydrogen exchanger (NHE) is a transmembrane protein responsible for alkalinization and control of intracellular acidosis by the removal of hydrogen and the subsequent influx of sodium. Our investigation attempts to determine the role of NHE‐1 in the pathogenesis of early retinal microangiopathy due to diabetes.