Dr. Dao-Fu Dai received a five-year NIH R01 award entitled ‘Metabolic Reprogramming and FGF21 Signaling in Kidney Health and Polycystic Kidney Diseases’ from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease caused by mutations in the PKD1 or PKD2 genes. Many patients often lose kidney function due to limited therapies to delay disease progression. The kidney is a highly metabolically active organ that relies on specialized tubular epithelial cells to reabsorb most of the filtered water and solutes in the body. Normal kidney tubules are highly enriched in mitochondria and preferentially use fatty acid oxidation (FAO), which generates more adenosine triphosphate (ATP) than glucose metabolism. However, one hallmark of metabolic derangement in ADPKD is decreased fatty acid oxidation (FAO) and increased aerobic glycolysis (Warburg effect). This metabolic derangement supports the growth of cysts that eventually lead to renal failure. We propose to study: 1) the role of enhancing FAO in delaying progression of ADPKD, 2) the role of ketogenic diet, FGF21 signaling and ketone body oxidation in ADPKD. Although dietary restrictions, such as time-restricted feeding or the condition of ketosis have been shown to ameliorate renal cyst progression in animal models of PKD1 mutation, the detailed molecular mechanisms are not fully elucidated. The clinical application of long-term dietary intervention is challenging because of non-compliance and high dropout rates. There is, therefore, a critical need to determine the roles of metabolic reprogramming and the molecular mechanisms underlying beneficial effects of dietary intervention, such as a ketogenic diet. We propose to investigate the effect of 5 genetic mouse models of enhanced FAO, decreased FGF21 signaling or impaired ketone body oxidation in the kidney-tubule specific PKD1 deletion mouse model of ADPKD. The metabolic status will be elucidated using metabolic flux analysis, metabolomics and targeted proteomics of metabolic proteins. In addition to mouse experiments, mechanistic studies will be performed using human cell lines with the PKD1 mutation.