This proposal seeks to investigate the roles of zinc, oxidative stress and dietary sodium in stone formation using a novel model of nephrolithiasis. Inhibition of Xanthine Dehydrogenase (XDH) in the fly results in increased concretion formation in the malpighian tubules, the functional equivalent of the human convoluted tubule. These concretions are both structurally and chemically similar to human Randall's plaques, structures believed to be the precursors to human kidney stones. Upon XDH inhibition, significantly more stones are observed in flies fed supplemented with zinc or deficient in the sodium/glucose transporter SLC5A11. The role of zinc homeostasis and oxidative stress will be investigated. Zinc is found in abundance in both Drosophila stones and Randall's plaques. Treating XDH inhibited flies with a zinc chelator results in significantly less concretions, therefore zinc may e a key factor mediating the initiation of stone formation.
The first aim of this proposal will examie the effects of bioavailable zinc on fly stone formation. Metallothioneins, proteins that regulate zinc homeostasis, will be genetically manipulated and the resulting effects on stone formation and malpighian tubule zinc content will be evaluated. Oxidative stress and reactive oxygen species (ROS) cause the release of zinc from Metallothionein and, oxidative stress has been associated with kidney stone disease. The proposed experiments will test the role of oxidative stress in Drosophila stone formation and zinc bioavailability.
The second aim of this proposal will address the potential mechanisms responsible for increased incidence of stone disease that correlates to high dietary sodium intake. We have identified two sodium transporters that modulate stone formation in our XDH fly model. We will investigate the role of sodium in malpighian tubule calcium excretion and fly stone formation This proposed research will shed light on the mechanisms responsible for the increased stone formation associated with dietary sodium and oxidative stress. Moreover, these proposed experiments may help to explain the association between metabolic diseases like obesity and diabetes with increased stone formation. Obesity, diabetes and kidney stone disease are all associated with increased oxidative stress therefore, oxidative stress may be a key physiological process linking these diseases.
Kidney stone disease is a significant source of morbidity and cost in the United States and mortality in the developing world. While there is a significant amount of epidemiological data suggesting links between diet, metabolic diseases and kidney stone formation, mechanistic and therapeutic advances have been lacking. We have developed a novel model of urinary stone disease using Drosophila melanogaster. We propose to use our model to study the impacts of dietary sodium, zinc, and oxidative stress in kidney stone formation.
|Chi, Thomas; Kim, Man Su; Lang, Sven et al. (2015) A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease. PLoS One 10:e0124150|