Cellular and Molecular Mechanisms of COVID-19 Mediated Kidney Injury

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PROJECT SUMMARY / ABSTRACT The ongoing coronavirus 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), and has led to over one million reported cases, significant morbidity and mortality, and extensive economic and societal disruption. The development of the disease has shown to lead to complications kidney failure. It is becoming clear that multiple mechanisms of kidney involvement in COVID- 19 infection are operative. Between 30 and 40% of severely infected COVID-19 patients develop Acute Kidney Injury with a high proportion requiring dialysis therapy in the Intensive care Unit. Moreover, evidence from biopsy and autopsy studies is emerging that kidney podocytes, proximal tubular epithelial cells and endothelial cells may become infected with SARS‑CoV‑2. Emerging data demonstrate that COVID-19 podocyte injury leads to nephrotic syndrome, proximal tubular involvement leads to acute kidney injury, and endothelial involvement leads to thrombotic microangiopathy – thus COVID-19 kidney involvement can have protean clinical manifestations, analogous to the effects of HIV infection on the kidney. No specific treatment is currently validated for COVID-19 related kidney disease, and understanding the cell-specific molecular processes associated with COVID-19 in patients with kidney disease and diabetes can have a significant impact on public health. A better understanding of the mechanism will foster development of effective therapies beyond the supportive care in the intensive critical care unit, which is already critically important as many of these patients require dialysis-related therapy. Our group has pioneered the development of `human kidney- on-a-chip' microphysiological systems (MPS), which recapitulate critical aspects of kidney physiology, assess the mechanisms and response to injury, and test reparative mechanisms. We will deploy our existing MPS to understand the cellular and molecular mechanisms of COVID-19 mediated kidney injury, and test therapeutic strategies to prevent kidney injury and kidney failure due to SARS‑CoV‑2.