Grant: Operating Grant

Common diseases such as high blood pressure and diabetes lead to kidney injury, the formation of scar tissue and eventually kidney failure. The number of Canadians who either have kidney disease or are at risk is estimated to be 2 million. Although progress has been made in understanding the mechanisms of kidney injury, there are still large gaps in our knowledge. In the past years the role of highly specialized kidney cells, the tubular epithelium as both target and initiator of injury and scarring has been increasingly recognized. Chemical mediators called cytokines, that are released by immune cells or the epithelium itself can alter epithelial function and initiate harmful responses. Importantly, the intactness of the contacts between the epithelial cells is vital for normal functions, and their disruption is an early step in many diseases. The objective of this proposal is to investigate the mechanisms whereby tumor necrosis factor-alpha (TNF-alpha), a cytokine that mediates kidney injury in various diseases, can affect cell-cell contacts and augment responses to scar forming stimuli. We will study the molecular events that lead to TNF-alpha-induced rearrangement of the cell architecture (cytoskeleton) and the contraction apparatus (myosin) through a molecule called RhoA. The mechanism whereby TNF-alpha disrupts cell-cell contacts in the tubular epithelium will also be investigated. We will use various biochemical and fluorescent microscopic techniques in kidney tubule cell lines and develop novel methods to study activation and interactions of molecules involved in the effects of TNF-alpha. These studies will provide new information about the mechanisms of epithelial injury. This knowledge will help understand how altered function can lead to kidney failure. Exploring the molecular interactions involved will offer novel targets for designing drugs to treat these currently untreatable conditions.