Single-cell RNA Sequencing Data Suggest a Role for Angiotensin-Converting Enzyme 2 in Kidney Impairment in Patients Infected with 2019-Novel Coronavirus
The 2019-novel coronavirus (2019-nCoV), declared a global public health emergency by the World Health Organization, has been primarily associated with respiratory symptoms. However, emerging evidence suggests that the virus affects multiple organs, including the kidneys. This article explores the role of angiotensin-converting enzyme 2 (ACE2) in kidney impairment among patients infected with 2019-nCoV, based on single-cell RNA sequencing data and immunohistochemical findings.
Background and Clinical Observations
Early clinical reports highlighted the occurrence of acute kidney injury (AKI) in patients infected with 2019-nCoV. Huang et al. reported that 7% of 41 patients exhibited AKI, with the incidence rising to 31% among intensive care patients. Li et al. observed increased plasma creatinine levels in 11 out of 59 patients, indicating impaired kidney function as the disease progressed. Similarly, Guan et al. noted elevated plasma creatinine levels in 4.3% of severely ill patients. These findings underscore the potential for kidney involvement in 2019-nCoV infections.
ACE2 and TMPRSS2: Key Players in Viral Entry
The entry of 2019-nCoV into target cells is mediated by ACE2, a receptor shared with the severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Additionally, the cellular protease transmembrane protease serine 2 (TMPRSS2) plays a crucial role in cleaving and activating the viral spike protein, facilitating membrane fusion. Given the expression of ACE2 and TMPRSS2 in various tissues, it is essential to investigate their presence in kidney cells to understand the mechanisms underlying kidney impairment in 2019-nCoV patients.
Single-cell RNA Sequencing Analysis
To determine the expression of ACE2 and TMPRSS2 in kidney cells, single-cell RNA sequencing data were obtained from the Gene Expression Omnibus (GEO) database and the Kidney Interactive Transcriptomics (KIT) database. The analysis included data from healthy donor kidney samples, para-carcinoma tissue from patients with tumors, and fetal kidney samples.
Healthy Donor Kidney Samples
Kidney samples from healthy donors, assigned the GEO accession numbers GSE109564 and GSE114156, revealed that ACE2 was predominantly expressed in proximal tubule cells. This finding was consistent across multiple datasets, indicating a specific localization of ACE2 in the kidney.
Para-carcinoma Tissue Samples
Data from para-carcinoma tissue samples, under the GEO accession number GSE131685, also showed that ACE2 was mainly expressed in proximal tubule cells. This consistency across different sample types reinforces the notion that ACE2 is a key receptor in kidney cells.
Fetal Kidney Samples
Analysis of fetal kidney samples from embryos aged 8 to 18 weeks demonstrated that ACE2 was expressed in tubular precursors. This suggests that ACE2 expression is established early in kidney development and persists into adulthood.
Immunohistochemical Validation
To corroborate the RNA sequencing findings, immunohistochemical staining data from the Human Protein Atlas were examined. ACE2 was found to be expressed in several human organs, including the intestines, adrenal gland, gallbladder, and kidneys. Notably, ACE2 was highly expressed in the urogenital and digestive systems, with significant staining observed in glandular cells of the intestine and gallbladder.
In the kidneys, ACE2 was predominantly expressed in the proximal tubules, aligning with the single-cell RNA sequencing data. However, in normal lung tissue, ACE2 showed only low expression levels, with some positive staining observed in lung macrophages. This raises questions about whether ACE2 expression increases in response to 2019-nCoV infection, warranting further investigation.
Implications for Kidney Impairment
The expression of ACE2 and TMPRSS2 in kidney cells indicates that the kidney is a potential target organ for 2019-nCoV. This finding has significant implications for understanding the pathogenesis of kidney impairment in infected patients. The high expression of ACE2 in proximal tubule cells suggests that these cells are particularly vulnerable to viral entry and subsequent damage.
Comparison with Other Coronaviruses
The role of ACE2 in kidney impairment is not unique to 2019-nCoV. Previous studies on SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV) have also highlighted the involvement of kidney cells. For instance, 6.7% of SARS-CoV patients exhibited AKI, with a median duration of 20 days and a mortality rate of up to 91.7%. Similarly, MERS-CoV was associated with AKI in 26.7% of patients, with the receptor DPP4 expressed in kidney cells such as tubule cells and podocytes.
The high expression of coronavirus receptors in kidney tubule cells underscores the kidney’s susceptibility to coronavirus infections. This emphasizes the need for targeted therapeutic strategies to prevent kidney damage in patients infected with 2019-nCoV.
Therapeutic Strategies
Given the expression of ACE2 and TMPRSS2 in kidney cells, therapeutic strategies targeting these molecules could be beneficial. Antibodies or biological inhibitors that block the viral spike protein, ACE2 receptor, or TMPRSS2 protease may prevent viral entry and mitigate kidney damage. Early interventions, including continuous renal replacement therapies, should be considered for patients showing signs of kidney failure, such as increased plasma creatinine levels.
Monitoring Kidney Function
Frequent monitoring of kidney function is crucial for patients infected with 2019-nCoV, particularly those with elevated plasma creatinine levels. Early detection of kidney impairment can facilitate timely interventions, preserving kidney function and improving patient outcomes. Indicators such as increased concentrations of urine protein, blood urea nitrogen, or plasma creatinine should prompt immediate clinical attention.
Conclusion
Single-cell RNA sequencing data and immunohistochemical findings provide compelling evidence for the role of ACE2 in kidney impairment among patients infected with 2019-nCoV. The high expression of ACE2 in proximal tubule cells highlights the kidney’s vulnerability to viral entry and subsequent damage. These insights underscore the need for targeted therapeutic strategies and vigilant monitoring of kidney function in infected patients. Understanding the mechanisms underlying kidney impairment in 2019-nCoV infections is essential for developing effective treatments and improving patient outcomes.
doi.org/10.1097/CM9.0000000000000783
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