Grant: Project Grant

Diabetes is a very common cause of kidney failure, leading to scarring of the filtering units of the kidneys. High glucose causes kidney cells called mesangial cells to make a protein called transforming growth factor beta (TGFbeta) which induces cells to make scar proteins. We previously showed that a protein called Akt is needed for mesangial cells to make TGFbeta and scar proteins. In order for Akt to do this, it has to be "turned on" or activated. In studying how this happens, we found that a protein called GRP78 is important. Normally found inside the cell, GRP78 also moves to the outside of the cell when it is exposed to high glucose. Here, it works with other proteins to activate Akt. Importantly, we also found that GRP78 outside of the cell may participate in allowing TGFbeta to be more effective at inducing cells to make scar proteins. In this project we will investigate how GRP78 can regulate these processes. We also found that a small molecule, vaspin, can block the effects of GRP78 on the outside of the cell. This is important since it provides us with an opportunity to test whether treating mice with diabetes with vaspin can inhibit or delay the development of kidney disease.