Vascular dysfunction and diabetets kideny disease

Dr. Mogher Khamaisi

A. The major project to be carried out over the next five years is to characterize the endothelin/ endothelin-converting enzyme system (ECE-1) in the diabetic kidney and its relevance to diabetes-associated vascular dysfunction. This includes understanding the activity, gene and protein expression of this system in the different parts of the diabetic kidney, and determining the intracellular signaling pathways, including the protein kinase C (PKC) pathway, the mitogen-activated protein kinase (MAPK) family, and phosphatidylinositol 3-kinase (PI3K), by which high glucose induces elevation in ECE-1 expression. 
Based on our findings in the experiments detailed above, we intend to address other questions related to the high glucose-induced elevation in ECE-1 expression, including: (a) What is the role of oxidative stress in the glucose-mediated elevation in ECE-1 expression? (b) Can in vivo antioxidant therapy affect ECE-1 expression and the associated diabetic vascular complications? (c) What is the role of tyrosine phosphorylation in PKC activation? (d) Are other tyrosine kinases, such as c-Src and Janks kinase 2 and 3 (JAK2 and JAK3), involved in PKC activation and ECE-1 expression? Answering these questions will involve pharmacogenetic approaches.
In order to determine the vitality of the endothelin system and its causative effect in the pathogenesis of vascular dysfunction, we plan to develop a new endothelin-converting enzyme knock-out rat model and evaluate whether these animals are protected from the diabetes-associated vascular dysfunction and kidney disease.
This research may yield enough data in the near future to promote the development of new pharmaco-therapy modalities such as the endothelin-converting enzyme inhibitors and/or antagonists, or, alternatively, new drugs that inhibit the intracellular components involved in the high glucose-induced activation of the endothelin system.
B. In parallel, we will attempt to understand the characterization of the endothelin system and its role in the development of contrast nephropathy in the diabetic patients. Understanding this system may help clinicians to better prepare the patient before exposure to contrast media and may reduce in-hospital acute renal failure.   This issue has a profound effect on global morbidity and mortality.
C. Today, there is no data concerning the spread of metabolic syndrome, obesity and diabetes in the Arab sub-population in the area. Epidemiological studies in this field are required. Hopefully, in the near future, in collaboration with the Department of Social Health, we shall conduct such studies.