Exploring the potential mechanisms of impairment on genitourinary system associated with coronavirus disease 2019 infection: Bioinformatics and molecular simulation analyses

doi:10.1016/j.ajur.2022.12.004

Asian Journal of Urology, 2023, 10 (3): 344-355 doi: 10.1016/j.ajur.2022.12.004

Original Article

Exploring the potential mechanisms of impairment on genitourinary system associated with coronavirus disease 2019 infection: Bioinformatics and molecular simulation analyses

Kai Zhao^a,b,Dong Zhang^a,b,Xinchi Xu^a,b,Shangqian Wang^a,b,Zhanpeng Liu^a,b,Xiaohan Ren^a,b,Xu Zhang^a,b,Zhongwen Lu^a,b,Shancheng Ren^c,*(

),Chao Qin^a,b,*(

)

^a Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
^b The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China
^c Department of Urology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China

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Abstract

Objective The novel coronavirus (severe acute respiratory syndrome coronavirus 2) has been spreading worldwide since December 2019, posing a serious danger to human health and socioeconomic development. A large number of clinical trials have revealed that coronavirus disease 2019 (COVID-19) results in multi-organ damage including the urogenital system. This study aimed to explore the potential mechanisms of genitourinary damage associated with COVID-19 infection through bioinformatics and molecular simulation analysis.
Methods We used multiple publicly available databases to explore the expression patterns of angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and CD147 in major organs in the healthy and disease-specific populations, particularly the genitourinary organs. Single-cell RNA sequencing was used to analyze the cell-specific expression patterns of ACE2, TMPRSS2, CD147, cytokine receptors, and cytokine interacting proteins in genitourinary organs, such as the bladder, kidney, prostate, and testis. Additionally, gene set enrichment analysis was used to investigate the relationship between testosterone levels and COVID-19 vulnerability in patients with prostate cancer.
Results The results revealed that ACE2, TMPRSS2, and CD147 were highly expressed in normal urogenital organs. Then, they were also highly expressed in multiple tumors and chronic kidney diseases. Additionally, ACE2, TMPRSS2, and CD147 were significantly expressed in a range of cells in urogenital organs according to single-cell RNA sequencing. Cytokine receptors and cytokine interacting proteins, especially CCL2, JUN, and TIMP1, were commonly highly expressed in urogenital organs. Finally, gene set enrichment analysis results showed that high testosterone levels in prostate cancer patients were significantly related to the JAK-STAT signaling pathway and the Toll-like receptor signaling pathway which were associated with COVID-19.
Conclusion Our study provides new insights into the potential mechanisms of severe acute respiratory syndrome coronavirus 2 damage to urogenital organs from multiple perspectives, which may draw the attention of urologists to COVID-19 and contribute to the development of targeted drugs.

Key words： Coronavirus disease 2019 Severe acute respiratory syndrome coronavirus 2 Angiotensin-converting enzyme 2 Transmembrane serine protease 2 CD147 Genitourinary organ Testosterone

Received: 27 August 2022 Available online:

Corresponding Authors: Shancheng Ren,Chao Qin E-mail: renshancheng@gmail.com;nmuqinchao@163.com

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	Kai Zhao
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	Zhongwen Lu
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	Chao Qin

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Cite this article:

Kai Zhao,Dong Zhang,Xinchi Xu, et al. Exploring the potential mechanisms of impairment on genitourinary system associated with coronavirus disease 2019 infection: Bioinformatics and molecular simulation analyses[J]. Asian Journal of Urology, 2023, 10(3): 344-355.

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http://www.ajurology.com/EN/10.1016/j.ajur.2022.12.004 OR http://www.ajurology.com/EN/Y2023/V10/I3/344

The expression of ACE2, TMPRSS2, and CD147 in normal human tissue from multiple public databases. (A) The mRNA expression pattern of ACE2 in HPA, GTEx, and FANTOM5; (B) The protein expression pattern of ACE2 in HPA; (C) The mRNA expression pattern of TMPRSS2 in HPA, GTEx, and FANTOM5; (D) The protein expression pattern of TMPRSS2 in HPA; (E) The mRNA expression pattern of CD147 in GTEx; (F) The protein expression pattern of CD147 in HPA. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane serine protease 2; HPA, Human Protein Atlas; GTEx, the genotype-tissue Expression; FANTOM5, the Functional Annotation Of The Mammalian Genome.

The ACE2 and CD147 protein concentration and distribution between male and female in plasma. (A and B) The concentration of ACE2 and CD147 in human plasma is quantified by mass spectrometry-based plasma proteomics and estimated from spectral counts in a publicly available data set obtained from the PeptideAtlas (ACE2: 400 ng/L, CD147: 340 ng/L); (C and D) Violin plot showing the distribution of ACE2 and CD147 between male and female in plasma, based on proximity extension assays (Olink) for a longitudinal wellness study covering 76 individuals with three visits during 2 years; and protein expression levels are reported as NPX. ACE2, angiotensin-converting enzyme 2; NPX, normalized protein expression.

Expression patterns of ACE2, TMPRSS2, and CD147 mRNA in specific patient populations. (A) The mRNA expression patterns of ACE2 in 33 kinds of tumors in TCGA; (B) Differential mRNA expression of ACE2 in 33 kinds of tumor tissue and normal tissue from TCGA; (C) The mRNA expression patterns of TMPRSS2 in 33 kinds of tumors in TCGA; (D) Differential mRNA expression of TMPRSS2 in 33 kinds of tumor tissue and normal tissue from TCGA; (E) The mRNA expression patterns of CD147 in 33 kinds of tumors in TCGA; (F) Differential mRNA expression of CD147 in 33 kinds of tumor tissue and normal tissue from TCGA; (G) The mRNA expression patterns of ACE2 in GSE66494; (H) The mRNA expression patterns of TMPRSS2 in GSE66494; (I) The mRNA expression patterns of CD147 in GSE66494. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane serine protease 2; CKD, chronic kidney disease; ns, no significant. ?p<0.05, ??p<0.01, ???p<0.001, ????p<0.0001.

Cell-specific mRNA expressions of ACE2, TMPRSS2, and CD147 in bladder, kidney, prostate, and testis. (A) Cell-specific expression of ACE2 from Human Cell Landscape Kidney2 (http://bis.zju.edu.cn/HCL/search.html); (B) Cell-specific expression of ACE2 from Human Cell Landscape Testis_Guo (http://bis.zju.edu.cn/HCL/search.html); (C) Cell-specific expression of TMPRSS2 from Human Cell Landscape Kidney2 (http://bis.zju.edu.cn/HCL/search.html); (D) Cell-specific expression of TMPRSS2 from Human Cell Landscape Prostate1 (http://bis.zju.edu.cn/HCL/search.html); (E) Cell-specific expression of TMPRSS2 from Human Cell Landscape Testis_Guo (http://bis.zju.edu.cn/HCL/search.html); (F) Cell-specific expression of CD147 from Human Cell Landscape Bladder1 (http://bis.zju.edu.cn/HCL/search.html); (G) Cell-specific expression of CD147 from Human Cell Landscape Kidney2 (http://bis.zju.edu.cn/HCL/search.html); (H) Cell-specific expression of CD147 from Human Cell Landscape Prostate1 (http://bis.zju.edu.cn/HCL/search.html); (I) Cell-specific expression of CD147 from Human Cell Landscape Testis_Guo (http://bis.zju.edu.cn/HCL/search.html). ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane serine protease 2; HPA, Human Protein Atlas; GTEx, the Genotype-Tissue Expression; FANTOM5, the Functional Annotation of The Mammalian Genome.

Cell-specific expression of cytokine receptors and cytokine interacting proteins in bladder, kidney, prostate, and testis. (A) Cell-specific expression of cytokine receptors and cytokine interacting proteins from Human Cell Landscape Bladder1 (http://bis.zju.edu.cn/HCL/search.html); (B) Cell-specific expression of cytokine receptors and cytokine interacting proteins from Human Cell Landscape Kidney2 (http://bis.zju.edu.cn/HCL/search.html); (C) Cell-specific expression of cytokine receptors and cytokine interacting proteins from Human Cell Landscape Prostate1 (http://bis.zju.edu.cn/HCL/search.html); (D) Cell-specific expression of cytokine receptors and cytokine interacting proteins from Human Cell Landscape Testis_Guo (http://bis.zju.edu.cn/HCL/search.html).

GSEA enrichment plots of GSE72920 dataset. (A) GSEA enrichment plot: JAK-STAT signaling pathway; (B) GSEA enrichment plot: Toll-like receptor signaling pathway. GSEA, Gene Set Enrichment Analysis; JAK-STAT, Janus kinase-signal transducers and activators of transcription.

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