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2025 Oxford-Harrington Rare Disease Scholar Award
Nephrology, Endocrine, Metabolic
Discovery of FATP2 Small Molecule Inhibitors to Treat Diabetic Kidney Disease
2023 Harrington Scholar-Innovator
Diabetic kidney disease is the most common cause of end-stage kidney disease. In pre-clinical studies, Dr. Schelling and his colleagues have found that small molecule inhibitors of a novel target, fatty acid transport protein-2 (FATP2), may offer a new treatment option.
Dr. Schelling explained that the kidney can be thought of as a filter with two components: the glomerulus and the tubules. Plasma is filtered across the glomerulus, and the tubules turn that plasma into urine. Loss of tubules is a strong predictor of kidney disease progression. The tubules have two sides: apical (urinary side) and basolateral (blood side). The proximal tubules derive energy by burning fatty acids taken from the basolateral side of the tubule.
“This system works fine until you have a disease such as diabetes where the glomerulus is injured, and now it’s exposing the apical tubule membranes to things that a healthy glomerulus would exclude,” Dr. Schelling said.
In diabetic kidney disease, fatty acids leak across the damaged glomerulus and are reabsorbed by the proximal tubule, where the simultaneous basolateral and apical fatty acid uptake is toxic. Dr. Schelling and his team have characterized apical FATP2 as the major transporter of fatty acid reabsorption, and have found that global FATP2 deletion in mice resulted in a dramatic reduction in plasma glucose, improved kidney histology, normalization of glomerular filtration rate and greater life expectancy.
“Targeting FATP2 is a completely different approach than existing therapies,” Dr. Schelling said. “Although it may not be a cure for diabetic kidney disease, it potentially represents a new option to prevent patients from progressing to end-stage kidney disease.”