Grant: Operating Grant

Common conditions such as high blood pressure and diabetes compromise kidney functions leading to kidney disease and failure. The number of Canadians living with or are at risk of developing kidney disease is estimated to be 2 million. Although progress has been made in understanding how kidney disease develops, there are still large gaps in our knowledge. The role of highly specialized kidney cells, the tubular epithelium in disease generation is now increasingly recognized. Chemicals released by immune cells or the epithelium itself alter epithelial function and initiate harmful responses. Importantly, the intactness of the cell architecture, the so called cytoskeleton, is vital for normal functions, and its disruption is an early step in many diseases. The objective of this proposal is to investigate how the chemical named Tumor Necrosis Factor-alpha (TNF-alpha) alters tubular cell functions and causes injury in the kidney. This molecule plays an important role in kidney disease, and affects tubular cell architecture and functions. We will study the molecular events that lead to activation of molecules involved in the regulation of cell architecture, integrity of junctions and many other vital functions including injury repair. We will focus on the cellular molecules called RhoA and their regulator GEF-H1, as these have central roles in many cell functions. They are regulated by harmful stimuli, but the details of the ensuing events are not well known. Therefore, we will use various biochemical, cell biological and fluorescent microscopic techniques in kidney tubule cell lines to study these molecules. We will also test our findings in animal models of kidney diseases. These studies will provide new information about the mechanisms of chronic kidney disease, with the hope of finding novel targets for designing drugs for these currently untreatable conditions.