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Abstract: SA-OR05

Genomic Datasets from Traditional Murine Models of AKI and AKI-Lung Cross-Talk Reveal Molecular Pathways Relevant to COVID-19 Infection

Session Information

Category: Coronavirus (COVID-19)

  • 000 Coronavirus (COVID-19)

Authors

  • Grigoryev, Dmitry N., University of Chicago Division of Biological Sciences, Chicago, Illinois, United States
  • Rabb, Hamid, Johns Hopkins Medicine, Baltimore, Maryland, United States
Background

COVID-19 infection leads to ARDS and AKI, and there are established mechanistic links between acute kidney injury (AKI) and lung injury. SARS-CoV-2 uses for cell entry angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), which are expressed in kidney and lung. Using publicly available genomics data of ischemic and sepsis induced AKI in mice, we searched for established and novel molecular players of AKI and AKI-lung cross-talk relevant to COVID-19.

Methods

The microarray datasets GSE6730 (AJP Renal 2007, JASN 2008) and GSE60088 (Shock 2016) were downloaded from Gene Expression Omnibus (GEO). GSE6730: lungs from mice with moderate and severe ischemic AKI were studied at 6h and 36h. GSE60088: kidneys were studied from mice after 6h of pneumonia+mechanical ventilation (PMV). Isolated RNA was hybridized to MG_430 microarray. To identify differentially expressed genes, GEO-built in GEO2R tool was used.

Results

AKI led to downregulated kidney ACE2 gene at both 6h (fold change (FC)=-2.41) and 36h (FC=-3.23) after severe (60min clamp) but not moderate ischemia (30 min clamp; 6 h: FC=-1.3, 36h: FC=-1.16). In lung from AKI mice, ACE2 was significantly downregulated (FC=-2.89, P=5.56*10-5). Ischemic AKI and PMV led to a decrease in lung TMPRSS2 FC=-1.83, P=1.19*10-2 and FC=-1.68, P=6.58*10-6, respectively. The filtering for known genes with P-value<0.01 and FC>4 identified 53 kidney genes upregulated by PMV; and 254 lung genes upregulated by AKI, of which 9 genes were common to both organs. 3 of 9 genes were previously linked to kidney-lung cross-talk: Lcn2 (FCLung=18.6, FCKidney=6.32), Socs3 (FCL=10.5, FCK=10.4), Inhbb (FCL=6.20, FCK=6.17). This finding validates our approach and makes other 6 genes appealing candidates, especially Maff (FCL=7.21, FCK=5.98). This gene participates in the cellular stress response and also binds the oxytocin receptor promoter, which may be involved in gender differences in disease severity.

Conclusion

We identified changes in COVID-19 related genes ACE2 and TMPRSS2 in traditional mouse models of AKI and lung cross talk. We also found new candidate genes activated in kidney during pneumonia+mechanical ventilation and in lung during AKI, which warrants further investigation of their involvement in the combined kidney-lung injury during COVID-19.