Cell Signaling Pathways Contributing to Abnormal Energy Metabolism in ADPKD and Its Therapeutic Targeting
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), a Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area, is the most common inherited kidney disease in humans, affecting nearly 1 in every 400-1000 individuals. It is caused by loss of function of one of two interacting proteins called polycystin-1 (PC1) and polycystin-2 (PC2). Affected kidneys develop small cysts, which progressively enlarge, ultimately leading to total loss of kidney function. In the US, approximately 10% of all cases of renal failure requiring hemodialysis or transplantation are caused by ADPKD. There are currently no approved drugs for this disease. Recent research revealed that kidney cells that line the cysts show substantial abnormalities metabolizing blood sugar to generate energy. Furthermore, preventing these cells from metabolizing the sugar using a sugar analog that cannot be metabolized appeared to slow the growth of kidney cysts in a mouse model of ADPKD. However, we find that sugar is not the only source used by these cells for energy metabolism, and the dose of the sugar analog used is clinically intolerable. We have also found that a cell adhesion receptor called integrin ß1 is responsible for the abnormal metabolism in PC1-deficient mouse cells and that its activity appears to be channeled through an enzyme that is selectively expressed in PC1-lacking mouse cells. Furthermore, we have shown that a drug that inhibits this enzyme ameliorated abnormal energy metabolism in the PC1-lacking mouse cells. This drug has been used previously in humans for other applications and was well tolerated. The proposed research is aimed at extending these observations to PC2-deficient cells and to primary human ADPKD cells, elucidating the specific integrin ß1 cystogenic pathways involved, and testing the identified drug in a mouse model of ADPKD. If successful, these studies should provide new insights into the cellular pathway(s) that underlie abnormal energy metabolism and cyst formation in ADPKD and could be translated into a clinical trial.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710407
Entities
People
- M. Amin Arnaout
Organizations
- Massachusetts General Hospital
- United States Army