Investigating ATP citrate lyase (ACLY) in chronic kidney disease
Lay Abstract
Chronic kidney disease (CKD) is common in North America. It increases the risk of kidney failure as well as heart disease, important causes of death and reduced enjoyment of life. Although we have some good treatments that help to delay worsening of kidney disease, improved treatments are still needed so that we can prevent kidney failure from developing. We and others have shown that a protein called ACLY (ATP citrate lyase) is increased in the kidneys of animals and humans with CKD. We have also shown that inhibiting ACLY decreases scarring and inflammation in a mouse model of CKD. We don’t yet fully understand how ACLY improves scarring. Previous studies showed that cells in the kidney with CKD don’t use energy properly. Since the increased ACLY may be a major reason for this change, we will study whether blocking ACLY function can improve energy use by kidney cells. Improving energy use would protect kidney cells from dying and prevent them from making scar proteins. We will also test whether ACLY in specific cells of the immune system called macrophages are important to scarring in CKD. We will use mice that we created that have ACLY removed only from macrophages, and see whether scarring is reduced in our CKD mouse model. This will help us better understand the effects of blocking ACLY in the immune system. Since diabetic kidney disease is the most common cause of kidney failure in North America, we will also see whether blocking ACLY will decrease scarring and improve kidney function in mice with type 2 diabetes. Using genetic information we have from large studies in diabetic patients, we will also see whether certain differences in the ACLY gene can be linked with a lower risk of diabetic kidney disease. Both will help to tell us whether more patients can benefit from this potential new treatment. This project brings together the experience of Dr. J. Krepinsky, an expert in studying diabetic kidney disease, Dr. G. Steinberg, an expert in Metabolic Diseases (studying how cells use energy) and in ACLY biology, as well as Dr. M. Lanktree (studying the genetics of ACLY in patients). Together, these studies will help us to better understand how ACLY can benefit CKD, and will tell us whether blocking ACLY function could also be a possible new treatment to treat diabetic kidney disease.
