Evaluating the Impact of Microgravity on a Microphysiologic Model of Kidney Stone Disease

• Main Author: Jones-Isaac, Kendan A
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2023
• Subjects: Cellular biology; Pharmaceutical sciences; Toxicology
• ISBN: 9798379910372

The kidney is a key organ for filtering of waste products as well as elimination of drugs and their metabolites. The kidney also plays an important role in mediating calcium homeostasis and bone mineralization by through the bioactivation of calcitriol (25-hydroxyvitamin D3) to 1a,25-dihydroxyvitamin D3). Kidney dysfunction results in a range serious medical conditions including osteoporosis and nephrolithiasis (kidney stone disease, KSD). Understanding underlying pathophysiologic mechanisms of renal nephropathies and dysfunction can lead to improved modeling of disease states and novel avenues for pharmacotherapy. Microphysiological systems represent a novel, in vitro platform for studying organ-specific pathologies and drug-induced toxicities. We have developed a 3D microphysiological model of the human renal proximal tubule to study kidney function as well as biomarkers of developing pathologies. Our kidney microphysiologic model of the proximal tubule (PT-MPS) has been previously established as capable of both evaluating extent of cytotoxicity caused by a nephrotoxic agent and investigating the underlying mechanisms responsible. We utilized the kidney MPS to assess the impact of three pro-oxidative and nephrotoxic agents representing three potential sources of oxidative stress induced renal tubule injury. The antibiotic drug polymyxin, the plant-derived environment toxin aristolochic acid 1, and crystals of calcium oxalate monohydrate representing early-stage constituents of forming kidney stones were each evaluated for their impact on 2D and 3D proximal epithelial cell cultures. To model the early events underlying kidney stone disease progression, we evaluated the response of MPS cultured PTECs to conditions replicating the early stages of kidney stone formation, we challenged our kidney MPS with calcium oxalate monohydrate crystals. We aimed to identify biomarkers reflective of response to COM crystal exposure as identification of perturbed signaling/stress response pathways may serve to guide disease treatment possibilities. Due to characteristics of the crystals, they cannot perfuse through the MPS device. Therefore, we performed crystal exposure studies in the microgravity environment available abord the International Space Station National Laboratory. We hypothesized that in microgravity, the calcium oxalate crystals would evenly disperse within the treatment media allowing them access to the internal culture chamber within the MPS Devices. Our results confirm that microgravity does facilitate the access of COM crystals into the MPS devices allowing for direct exposure to MPS cultured PTECs. Renal dysfunction and progression of disease states is frequently accelerated and exacerbated in the microgravity. Our MPS model of kidney stone disease allowed us to investigate the effects of microgravity induced physiological alterations on kidney function and disease progression, given the known increased incidence of nephrolithiasis in a very healthy patient population-Cosmonauts and Astronauts.