The kidney's primary functions are to filter blood in the glomeruli, and retain or eliminate electrolytes, water and other solutes in the tubules. Damage to the kidney, via disease or toxin exposure, challenges the function of the kidney and can eventually result in renal fibrosis, chronic kidney disease and kidney failure. Current laboratory tools to study the kidney include monolayer cell cultures and animal models. Monolayer cell cultures do not fully mimic the human kidney as they lack three-dimensional structure and tissue-specific function. Animal models are inadequate to fully reproduce the patterns of injury seen in humans. Engineered, three- dimensional (3D) culture would be a highly relevant methods of in vitro exploration of kidney cell function, dysfunction and nephrotoxicity. The goal of this research is to explore 3D human renal proximal tubule (HRPT) tissue models containing renal proximal tubule epithelial cells (RPTECs), fibroblasts and monocytes to study tissue damage and disease progression. The 3D HRPT tissue model will a slowly degrading, porous silk fibroin scaffold with predefined channels. An extracellular matrix-hydrogel containing monocytes and renal fibroblast will be infused within the pores. The predefined channels will support epithelialization by RPTECs. This model will be perfusion cultured allowing for longer term cultures (six months), a substantial improvement to current 3D in vitro models which focus on relatively short (acute) responses. Our hypothesis is that the 3D HRPT tissue models can be used as tools to understand kidney tubule function, dysfunction in disease and toxicity, specifically the effects of inflammatory changes on injury and repair. To address this hypothesis, inflammation- induced renal fibrosis and nephrotoxicity will be investigated within the engineered tissues. Inflammation- induced renal fibrosis will be modeled by stimulating tissues with the inflammatory cytokine TNF-?. Nephrotoxin-induced tubule damage will be investigated using cyclosporine, gentamicin and cisplatin. The 3D HRPT tissue models will allow for investigation of both acute (short-term cultures) and chronic (long-term cultures) tissue responses. To assess tissue development and damage, we will characterize cell viability, proliferation and morphology, tissue structure and function, cytokine and extracellular matrix secretion, kidney injury biomarkers, and apoptosis and necrosis markers. The information garnered from this model will offer improved insight into disease pathology and progression. The model may also serve as a tool for drug discovery to identify therapeutic targets and nephrotoxicity. In the future, this model can be combined with other kidney structures and inflammatory cells to engineer a more complete kidney and more extensively model kidney diseases. Furthermore, the model can be extended to the engineering of other organs further broadening its applications.
Limited information on kidney damage and necessary clinical interventions to restore complete function can be acquired from current laboratory research tools, monolayer cell cultures and animal models. In vitro, three dimensional human kidney tissue models are needed to study kidney diseases and toxin-induced injuries. These models would offer insight into the mechanism of kidney damage, define new therapeutic targets and aid in drug discovery.
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