Electronic Thesis and Dissertation Repository

Thesis Format

Alternative Format

Degree

Master of Science

Program

Surgery

Supervisor

Razvi, Hassan

2nd Supervisor

Jennifer Bjazevic

Co-Supervisor

Abstract

Impaired cellular tolerance of reactive oxygen species (ROS) has been suggested as a common mechanistic link associated with aging in both metabolic syndrome and nephrolithiasis. The mechanistic (mammalian) target of rapamycin (mTOR) activity is characteristic of metabolic syndrome. When nutrients are abundant, mTOR is active. Conversely, fasting inhibits mTOR. Metabolic syndrome is correlated with an increased risk of self-reported or imaging findings of nephrolithiasis. At the individual level, patients with a higher BMI have an increased prevalence of recurrent symptomatic nephrolithiasis, 24-hour urinary excretion of oxalate, sodium, uric acid, calcium, and phosphorous as well as lower pH. Calcium oxalate crystals produce ROS in renal epithelial cells and upregulate ROS and also mTOR activity. Rapamycin pharmacologically inhibits mTOR leading to autophagy – a natural defense mechanism against ROS – and drives sub-cellular recycling machinery to a net catabolic state. Ideally, inhibiting mTOR limits the duration and degree of damage done by ROS and subsequent inflammatory process. Additionally, improved clearance of damaged organelles prevents runaway generation of ROS by mitochondrial dysfunction associated with calcium oxalate crystal adherence and internalization. Taken together, this may prevent the progression of calcium oxalate urolithiasis. In this study, we examined the effect of short-term intermittent rapamycin treatment on the area of calcium oxalate concretion in the Malpighian tubules of a Drosophila melanogaster fed a lithogenic diet containing 0.1% sodium oxalate.

Summary for Lay Audience

We do not know why obesity and aging are risk factors for kidney stones. A pathway called the mTOR pathway might help explain why older and more obese people form more stones compared to younger fit people. Our project found that using a drug (rapamycin) to slow down this pathway could lower the ability kidney stones to form in a fruit fly animal model. This finding suggests we should design more experiments to block this pathway either through specific diets, exercises, and/or drug treatments that might one day be tried in humans.

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