Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder where patients, over the course of decades, develop large fluid filled cysts that damage the normal kidney tissue and can lead ultimately to kidney failure that necessitates transplantation or dialysis. Treatment options are very limited for this condition. Recent research reveals that the formation of cysts is due in part both to inappropriate cell growth, fluid secretion, and dysregulation of cellular energy metabolism. The enzyme AMPK regulates a number of cellular pathways, including these disease-causing features. Drugs that activate AMPK, therefore, may constitute an effective therapeutic option for slowing or preventing cyst growth in ADPKD. This research project is aimed at examining the potential of approved, widely used, inexpensive and low-toxicity drugs that can activate AMPK (metformin, simvastatin, and salicylates) and or promote oxidative metabolism (dichloroacetic acid) as potential therapies for the treatment of ADPKD. Over the entire funding period of the grant, we measured and analyzed various metabolomic biomarkers in samples derived from cell lysates and urine, collected cyst growth data in ADPKD in vitro cell culture models and urine specimens derived from a broad cross-section of patients with ADPKD, and collected in vivo data on studies of metformin and salicylates, alone and in combination, for the treatment of ADPKD in mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2018
- Accession Number
- AD1074215
Entities
People
- Kenneth R. Hallows
- Michael J Caplan
Organizations
- University of Southern California