Title

Modeling Uric Acid Kidney Stones Disease in D. melanogaster using RNAi and Dietary Modulation

Graduation Date

5-2015

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Maggie Louie, Ph.D.

First Reader

Pankaj Kapahi, Ph.D.

Second Reader

Roland Cooper, Ph.D.

Abstract

In humans, the major predictor for gout and forming uric acid kidney stones is elevated uric acid in the serum and urine respectively. It is known that uric acid is an end metabolite of purine degradation in humans, but in other species from D. melanogaster to lower apes, uric acid can be further metabolized by urate oxidase into readily excreted allantoin. We hypothesize that if urate oxidase enzyme activity and dietary purine are both critical in uric acid kidney stone formation, then urate oxidase knockdown in combination with dietary purine supplementation will increase uric acid and induce uric acid kidney stone formation in D. melanogaster. Initially, we confirmed urate oxidase knockdown and then elevation of uric acid as a consequence. We then confirmed uric acid kidney stones formed as a consequence of urate oxidase knocked down and a high purine diet. Next, we tested compounds used to treat gout or uric acid kidney stones in humans using our model. We found that allopurinol and potassium citrate reduced uric acid kidney stone formation in our model. We then tested whether compounds predicted to reduce uric acid and uric acid kidney stones in humans, but not currently used as treatments, can reduce uric acid kidney stone formation in our model. We found that methotrexate, hydrochlorothiazide, and l-lysine were effective at reducing uric acid kidney stone formation. Lastly, we ran a medium throughput screen of 117 natural compounds for inhibitors of uric acid kidney stone formation using our model and found seven inhibitors.

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