The effect of mTOR inhibitor rapamycin on a dietary Drosophila melanogaster model of calcium oxalate nephrolithiasis

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.

Name thesis:degree_name

M Sc

Discipline thesis:degree_discipline

Surgery

Grantor dc:publisher

The University of Western Ontario

Year dc:date.issued

2020

Author dc:creator

• Pignanelli, Michael T

Advisors dc:contributor.advisor

• Razvi, Hassan
• Jennifer Bjazevic

• nephrolithiasis
• rapamycin
• mTOR
• Drosophila melanogaster
• calcium oxalate
• sodium oxalate
• Malpighian tubule
• aging
• metabolic syndrome
• reactive oxygen species
• autophagy.

Language dc:language.iso

en_ca

Handle dc:identifier.uri

https://hdl.handle.net/20.500.14721/30821

OAI identifier oai:identifier

oai:uwo.scholaris.ca:20.500.14721/30821