Kidneys are highly susceptible to various forms of injury and demonstrate a limited regenerative capacity. The development of acute kidney injury is often associated with risks for mortality and easily progresses into chronic kidney disease?which affects more than 26 million American adults. The peritubular capillaries are important for supporting tubular function but are highly susceptible to rarefaction following injury?which contributes directly to tubular dysfunction, fibrosis and the development of acute kidney injury and chronic kidney disease. Recently, we developed methods to isolate and study the behavior of human peritubular microvascular endothelial cells (HKMECs) in standard culture and in an engineered microphysiological system (Ligresti and Nagao, JASN, 2015). HKMECs demonstrated significant differences from human umbilical vein endothelial cells in molecular signatures, phenotype and angiogenic potential. To better recreate the native environment of HKMECs, we fabricated a hydrogel derived from human kidney cortex (Nagao, Tissue Eng, 2016). HKMECs became more quiescent when cultured on the kidney-derived hydrogel, and alternatively, became activated when cultured on a matrix comprising kidney cortex and collagen-I?a protein typically associated with fibrosis within the kidney. Here we will attempt to better understand the progression of kidney vascular disease by creating an engineered microvascular disease model. We will first further recapitulate the renal microvascular niche by incorporating stromal perivascular cells into our engineered HKMEC system. We will examine the hypothesis that perivascular cells will lead to vessel maturation. With our complete microphysiological system, we will investigate how physiological changes that occur within the microvascular niche during injury contribute to endothelial cells dysfunction. We hypothesize that changes to the surrounding extracellular matrix contributes to vascular dysfunction. We will characterize the extracellular matrix composition of human nephritic samples, then fabricate a new material that accurately reflects changes that occur during a fibrotic response. Lastly we will attempt to establish a 3D vascular microphysiological disease model. We hypothesize that disturbed flow that occurs during disease progression contributes to the poor regenerative capacity of kidney endothelial cells and will also examine the impact of nephrotoxic agents and fibrotic inducers for their individual influence on the multicellular microvascular niche.
Recent evidence has emerged that identifies renal vascular disease as a precursor to acute kidney injury and chronic kidney disease. The purpose of this proposal is to develop a framework for studying renal vascular disease by accurately reconstructing the renal microvascular niche in a microphysiological system that allows for the systematic study of the factors that contribute to vascular dysfunction. We anticipate that new findings will lead to the identification of novel therapies to renal vascular disease.
