Glomerulus on a Chip: A Model to Study Glomerular Hyperfiltration

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Project Summary/Abstract Approximately 34 million people in the United States suffer from Diabetes Mellitus. Some of the early complications of diabetes are glomerular hyperfiltration and hypertrophy. Despite being a temporary increase in kidney function, hyperfiltration progresses into irreversible damage to the glomerular filtration barrier (GFB) and nephron. Hyperfiltration is additionally one of the secondary effects of heart failure and can be a precipitating cause of progressive heart failure. Being able to stop the progression of glomerular hyperfiltration may help stem the development of diabetic kidney disease and congestive heart failure. As such, we seek to develop a physiomimetic Organ on a Chip model of the glomerular filtration barrier to aid in studying the progression of hyperfiltration. This model will help to facilitate an understanding of the cellular changes to the endothelial cells and podocytes that make up the glomerular filtration barrier. To mimic the GFB, we have co- cultured podocytes and endothelial cells on opposite sides of a porous collagen membrane scaffold. The membrane can be transplanted into our Organ on a Chip device, and media can be run across the basal and apical sides of the membrane in two separate channels. Our model can effectively recapitulate the effects of both causes of hyperfiltration, osmotic and hydrostatic. Our pressure control system on the chip allows us to control the hydrostatic pressure across our GFB, specifically adjusting the pressure in the apical and basal culture chambers. Alteration of the media protein concentrations allows for osmotic control. Modeling hyperfiltration will allow us to demonstrate the cytoskeletal changes, upregulation of cell-glomerular basement membrane attachment proteins, that occur in the podocytes and endothelial cells. Additionally, we will show that peak hyperfiltration will lead to scarring and buildup of membrane proteins in the GFB that will lead to decreased filtration as is seen in human hyperfiltration progression.