Project 452359

Injury is a key contributor to chronic kidney disease leading to scarring (fibrosis), and ultimately kidney failure. Diseases, such as high blood pressure and diabetes cause ongoing injury that result in kidney scarring. Although this is a huge public health problem, there are large gaps in our knowledge about how kidney scarring develops, and therefore we do not have ways to prevent or treat this condition. Our CIHR supported studies have contributed to new details of a crucial molecule, GEF-H1 and cells called tubular epithelia in kidney scarring. These highly specialized cells in the kidney have recently emerged as key initiators of regeneration from injury. However, their failed repair after injury contributes to scarring. Molecules, called cytokines, released upon injury cause long-term changes in the epithelium and the surrounding cells, which is a key trigger for disease. We previously showed that GEF-H1, a master regulator of the tubular structure and functional responses, is activated by injury-causing stimuli and is key for orchestrating a response to injury. Its inappropriate regulation can be central to kidney disease. During organ scarring the abundance of GEF-H1 increases, which could contribute to the development of the disease. The objective of this proposal is to determine how GEF-H1 is altered by triggers that cause kidney scarring, and to get in depth insight into the role of this important molecule. Using biochemical, cell biological and fluorescent microscopic approaches in cultured kidney cell models, and in kidney disease animal models, we will define an entirely new molecular pathway mediating disease-causing activation and effects of GEF-H1. These studies will provide new information about the mechanisms of failed healing during kidney scarring, and will help uncover novel drug targets for treatment of chronic kidney disease, a condition affecting a large percentage of the population.