Graduation Date

5-2017

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Maggie Louie, PhD

First Reader

Pankah Kapahi, PhD

Second Reader

James Cunningham, PhD

Abstract

Cystinuria is an autosomal recessive genetic disorder characterized by the defect of a renal transporter involved in cystine reabsorption. When this transporter is deficient, cystine cannot be broken down and reabsorbed by the body and is excreted via urine in high concentrations. The high levels of cystine present in the urine eventually lead to recurrent cystine urolithiasis due to its inability to solubilize. Despite having various forms of treatments such as thiol pharmaceutical therapies such as tiopronin and urine alkalinizing agents like potassium citrate, only few patients with cystinuria are able to successfully decrease cystine urine concentration. We observed the effects of tiopronin on its ability to inhibit and prevent stone formation and found it to be only moderately effective. In addition to observing tiopronin as a therapeutic, we also looked into the effects of potassium citrate as a treatment. We found potassium citrate to have a varying effects on both urinary pH and stone formation. Recently, our lab had shown that the nutritional-supplement α lipoic acid was an effective inhibitor of cystine stone formation. Here, we continued to further confirm the effects of α lipoic acid as an inhibitor and preventer of stone growth. Due to the unknown mechanism of α lipoic acid, we hypothesized α lipoic acid to be promoting cystine reabsorption through the Nrf2 pathway. In our Slc3a1-/-; Nrf2-/- mouse model, the mice treated with α lipoic acid still continued to have a reduced rate of stone formation. These results suggested Nrf2 was not the pathway in which α lipoic acid was inhibiting stone growth. In addition, we observed the effects of the combination of potassium citrate and α lipoic acid since potassium citrate is a standard of care of cystinuric patients. Our results suggested there are no adverse effects when the two drugs are administered together.

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