Identification of common molecular signatures of SARS-CoV-2 infection and its influence on acute kidney injury and chronic kidney disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main cause of COVID-19, causing hundreds of millions of confirmed cases and more than 18.2 million deaths worldwide. Acute kidney injury (AKI) is a common complication of COVID-19 that leads to an increase in mortality, especially in intensive care unit (ICU) settings, and chronic kidney disease (CKD) is a high risk factor for COVID-19 and its related mortality. However, the underlying molecular mechanisms among AKI, CKD, and COVID-19 are unclear. Therefore, transcriptome analysis was performed to examine common pathways and molecular biomarkers for AKI, CKD, and COVID-19 in an attempt to understand the association of SARS-CoV-2 infection with AKI and CKD. Three RNA-seq datasets (GSE147507, GSE1563, and GSE66494) from the GEO database were used to detect differentially expressed genes (DEGs) for COVID-19 with AKI and CKD to search for shared pathways and candidate targets. A total of 17 common DEGs were confirmed, and their biological functions and signaling pathways were characterized by enrichment analysis. MAPK signaling, the structural pathway of interleukin 1 (IL-1), and the Toll-like receptor pathway appear to be involved in the occurrence of these diseases. Hub genes identified from the protein-protein interaction (PPI) network, including DUSP6, BHLHE40, RASGRP1, and TAB2, are potential therapeutic targets in COVID-19 with AKI and CKD. Common genes and pathways may play pathogenic roles in these three diseases mainly through the activation of immune inflammation. Networks of transcription factor (TF)-gene, miRNA-gene, and gene-disease interactions from the datasets were also constructed, and key gene regulators influencing the progression of these three diseases were further identified among the DEGs. Moreover, new drug targets were predicted based on these common DEGs, and molecular docking and molecular dynamics (MD) simulations were performed. Finally, a diagnostic model of COVID-19 was established based on these common DEGs. Taken together, the molecular and signaling pathways identified in this study may be related to the mechanisms by which SARS-CoV-2 infection affects renal function. These findings are significant for the effective treatment of COVID-19 in patients with kidney diseases.

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1β, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

A survey on acute kidney injury in severely and critically ill COVID-19 patients without chronic kidney disease.

BACKGROUND: Research has shown that acute kidney injury (AKI) has a noticeable incidence in critically ill patients with coronavirus disease 2019 (COVID-19). Patients with prior renal insufficiency are particularly susceptible to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), due to their immune dysfunction. However, most patients with COVID-19 do not have a history of kidney dysfunction, and few studies have focused on the incidence of AKI among COVID-19 patients without chronic kidney disease (CKD). In this study, we aimed to investigate the occurrence of AKI in severely and critically ill COVID-19 patients, with a particular focus on those without a CKD history. METHODS: A single-center retrospective study of 96 patients with COVID-19 in China between February 7 and March 3, 2020 was conducted. All patients were diagnosed by nucleic acid test (NAT) for SARS-CoV-2. Enrolled patients were divided into the severely or critically ill group according to the defined criteria. Patients' epidemiological, clinical, and laboratory characteristics, along with their treatment information, were collected from the medical history system. The occurrence of AKI was compared between the severe and critical patients, and between patients with or without a history of CKD. The diagnostic criteria for AKI included an increase in the serum creatinine level to ≥1.5-fold the level at baseline within 7 days according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Renal outcomes were defined as AKI or non-AKI. RESULTS: Four patients (4.2%) developed AKI, all of whom were in the critically ill group, and 3 (75%) of whom died. Out of the 90 severely and critically ill COVID-19 patients without CKD, 3 (3.3%) patients developed AKI; out of the 6 patients with CKD, 1 (16.7%) patient developed AKI. Age, disease severity, procalcitonin, C-reactive protein, and interleukin-6 were correlated with AKI onset in severely and critically ill COVID-19 patients, while lymphocyte count and estimated glomerular filtration rate at admission were inversely related to the development of AKI. CONCLUSIONS: Only 3.3% of severely and critically ill COVID-19 patients without CKD in our research cohort developed AKI. Critically ill patients may be more susceptible to AKI than severely ill patients.