Cellular and Molecular Mechanisms of COVID-19 Mediated Kidney Injury

PROJECT SUMMARY / Abstract: The ongoing coronavirus 2019 (COVID-19) pandemic is caused by severe acute respiratory syndromecoronavirus 2 (SARS‑CoV‑2), and has led to over one million reported cases, significant morbidity andmortality, and extensive economic and societal disruption. The development of the disease has shown to leadto 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 KidneyInjury with a high proportion requiring dialysis therapy in the Intensive care Unit. Moreover, evidence frombiopsy and autopsy studies is emerging that kidney podocytes, proximal tubular epithelial cells and endothelialcells may become infected with SARS‑CoV‑2. Emerging data demonstrate that COVID-19 podocyte injuryleads to nephrotic syndrome, proximal tubular involvement leads to acute kidney injury, and endothelialinvolvement leads to thrombotic microangiopathy - thus COVID-19 kidney involvement can have proteanclinical manifestations, analogous to the effects of HIV infection on the kidney. No specific treatment iscurrently validated for COVID-19 related kidney disease, and understanding the cell-specific molecularprocesses associated with COVID-19 in patients with kidney disease and diabetes can have a significantimpact on public health. A better understanding of the mechanism will foster development of effective therapiesbeyond the supportive care in the intensive critical care unit, which is already critically important as many ofthese 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, assessthe mechanisms and response to injury, and test reparative mechanisms. We will deploy our existing MPS tounderstand the cellular and molecular mechanisms of COVID-19 mediated kidney injury, and test therapeuticstrategies to prevent kidney injury and kidney failure due to SARS‑CoV‑2.