High SARS-CoV-2 Viral Load in Urine Sediment Correlates with Acute Kidney Injury and Poor COVID-19 Outcome

Caceres, Paulo; Savickas, Gina; Murray, Shannon L; Umanath, Kausik; Uduman, Junior; Yee, Jerry; Liao, Tang-Dong; Bolin, Steven R.; Levin, Albert M.; Khan, Moomal N.; Sarkar, Sarah; Fitzgerald, Jamie M.; Maskey, Dipak; Ormsby, Adrian H.; Sharma, Yuvraj; Ortíz, Pablo

doi:10.1681/asn.2021010059

Cited by 30 publications

(26 citation statements)

References 48 publications

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“…This is supported by the finding that urinary SARS‐CoV‐2 and SARS‐CoV‐2 N protein can be detected in COVID‐19 patients with AKI and correlate with the AKI severity and mortality. [ 41 , 42 ] These clinical observations suggest the pathogenic role for SARS‐CoV‐2 N in AKI. Findings from the present study confirmed that this clinical notion unraveled the new role for SARS‐CoV‐2 N protein in the pathogenesis of AKI.…”

Section: Discussionmentioning

confidence: 95%

SARS‐CoV‐2 N Protein Induces Acute Kidney Injury via Smad3‐Dependent G1 Cell Cycle Arrest Mechanism

Wang

Chen

et al. 2021

Advanced Science

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COVID‐19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID‐19 and acute kidney injury (AKI) is common in critically ill COVID‐19 patients. However, mechanisms through which COVID‐19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney‐specifically overexpressing SARS‐CoV‐2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS‐CoV‐2 N‐induced AKI is Smad3‐dependent as SARS‐CoV‐2 N protein can interact with Smad3 and enhance TGF‐β/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS‐CoV‐2 N protein‐induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS‐CoV‐2 N‐induced AKI. In conclusion, the authors identify that SARS‐CoV‐2 N protein is a key mediator for AKI and induces AKI via the Smad3‐dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID‐19‐asscoaited AKI.

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Section: Discussionmentioning

confidence: 95%

SARS‐CoV‐2 N Protein Induces Acute Kidney Injury via Smad3‐Dependent G1 Cell Cycle Arrest Mechanism

Wang

Chen

et al. 2021

Advanced Science

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“…ACE2 is strongly expressed in kidney tubules [87,129,130]; SARS-CoV-2 can be detected in urine [131] and in autopsy kidney tissue from SARS-CoV-2-infected patients [132,133], and COVID-19 patients show signs of kidney damage [71,134,135]. To determine if the kidney function decline reported for COVID-19 patients could be due to the infection of kidney cells by SARS-CoV-2, hES-derived kidney epithelium organoids were interrogated.…”

Section: Kidneymentioning

confidence: 99%

Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which was classified as a pandemic in March 2020. As of 22 January 2022, globally more than 347 million cases of COVID-19 have been diagnosed, with 5.6 million deaths, making it the deadliest pandemic since the influenza pandemic in 1918. The clinical presentation of COVID-19-related illness spans from asymptomatic to mild respiratory symptoms akin to influenza infection to acute symptoms, including pneumonia necessitating hospitalisation and admission to intensive care units. COVID-19 starts in the upper respiratory tract and lungs but in severe cases can also involve the heart, blood vessels, brain, liver, kidneys and intestine. The increasing global health and economic burden of COVID-19 necessitates an urgent and global response. Understanding the functional characteristics and cellular tropism of SARS-CoV-2, and the pathogenesis that leads to multi-organ failure and death, has prompted an unprecedented adoption of organoid models. Successful drug discovery and vaccine development rely on pre-clinical models that faithfully recapitulate the viral life cycle and the host cell response to infection. Human stem cell-derived organoids fulfill these criteria. Here we highlight the role of organoids in the study of SARS-CoV-2 infection and modelling of COVID-19 pathogenesis.

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“…Severe COVID-19 disease is in fact frequently associated with kidney injury produced by both indirect mechanisms and direct damage due to virus replication [27,28]. Actually, SARS-CoV-2 has been found in autopsy specimens and urine samples [29,30], and its cellular receptor, ACE2, is highly expressed in renal tubules [31].…”

Section: Meds433 Affects Sars-cov-2 Replication In Kidney Organoidsmentioning

confidence: 99%

The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses

et al. 2021

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Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.

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High SARS-CoV-2 Viral Load in Urine Sediment Correlates with Acute Kidney Injury and Poor COVID-19 Outcome

Cited by 30 publications

References 48 publications

SARS‐CoV‐2 N Protein Induces Acute Kidney Injury via Smad3‐Dependent G1 Cell Cycle Arrest Mechanism

SARS‐CoV‐2 N Protein Induces Acute Kidney Injury via Smad3‐Dependent G1 Cell Cycle Arrest Mechanism

Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses

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