Grant: Project Grant

One in five people admitted to hospital develop acute kidney injury (AKI) and AKI is responsible for some 2 million deaths each year. Even if a person recovers from a bout of AKI, they are at increased risk of developing long-term damage to their kidneys. We urgently need new treatments. Our research team has discovered that a particular group of processes that goes on within cells plays an important role in the development of kidney disease. This group of processes is called "epigenetics". The term epigenetics refers to changes in the way genes carry the genetic code to make proteins that do not involve changes in the typical DNA code. For example, in order for each DNA strand to be packed inside of a cell, it has to be wrapped around spools of proteins called histones. If these spools are modified by chemical reactions this can affect how genes nearby make the proteins that they code for. Building on work we recently published, we have discovered that a particular chemical modification to histones (that normally happens in cells) is lost after AKI and that this loss predisposes to the development of AKI. In the present application, we will expand on our recent discoveries to explore the role of this histone modification in AKI and in the development of long-term kidney damage after AKI. We will perform experiments to maintain the histone modification in kidney cells grown in Petri dishes and in mice that develop AKI using both a pharmacological approach (a new drug) and a genetic approach (called cell-specific knockout mice). We will look to see whether this strategy improves outcomes after AKI caused by a reduced blood flow to the kidneys, a blockage to the outflow of the kidneys or a toxin (the three most common causes of AKI) and we will relate our findings to changes we see in human kidney samples. If the project is successful, it could lead to the development of a new treatment that could benefit the millions of people who develop AKI each year.