Suppression of Androgen Receptor (AR)-ACE2/TMPRSS2 Axis by AR Antagonists May Be Therapeutically Beneficial for Male COVID-19 Patients

Wu, Siqi; Miao, Liyan; Zhou, Qianxiang; Gao, Chang; Liu, Jialin; Zhan, Qingyuan; Guo, Binbin; Fang, Li; Wang, Yirong; Xu, Hongpeng; Yan, Honghua; Wu, Rui; Zhang, Shenghua; Zheng, Jiangnan; Yang, Jianfei; Wang, Shanshan; Yu, Wenkui; Niu, Haitao; Li, Fengyuan; Yang, Ling; Huang, Jianan; Lu, Xiaoting; Tong, Youzhi; Ma, Liandong; Zhou, Yifeng; Guo, Qiang

doi:10.2139/ssrn.3580526

Cited by 11 publications

(10 citation statements)

References 16 publications

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“…Another pre-print examining ACE2 expression throughout the urinary tract reported higher expression in testicular gametocytes and in renal proximal tubules [25]. Finally, Wu et al report in their pre-print, the relationship between androgen receptor activation and ACE2 and TMPRSS2 expression, and how this may contribute to the higher mortality from COVID-19 in males [26].…”

Section: Translationalmentioning

confidence: 98%

Scoping review: hotspots for COVID-19 urological research: what is being published and from where?

Perera

Lawrentschuk

et al. 2020

World J Urol

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Purpose Contemporary, original research should be utilised to inform guidelines in urology relating to the COVID-19 pandemic. This comprehensive review aimed to: identify all up-to-date original publications relating to urology and COVID-19, characterise where publications were from, and outline what topics were investigated. Methods This review utilised a search strategy that assessed five electronic databases, additional grey literature, and global trial registries. All current published, in-press, and pre-print manuscripts were included. Eligible studies were required to be original research articles of any study design, reporting on COVID-19 or urology, in any of study population, intervention, comparison, or outcomes. Included studies were reported in a narrative synthesis format. Data were summarised according to primary reported outcome topic. A world heatmap was generated to represent where included studies originated from. Results Of the 6617 search results, 48 studies met final inclusion criteria, including 8 pre-prints and 7 ongoing studies from online registries. These studies originated from ten countries according to first author affiliation. Most studies originated from China (n = 13), followed by Italy (n = 12) and USA (n = 11). Topics of the study included pathophysiological, administrative, and clinical fields: translational (n = 14), COVID-19-related outcomes (n = 5), urology training (n = 4), telemedicine (n = 7), equipment and safety (n = 2), urology in general (n = 4), uro-oncology (n = 3), urolithiasis (n = 1), and kidney transplantation (n = 8). Conclusion This review has outlined available original research relevant to COVID-19 and urology from the international community. This summary may serve as a guide for future research priorities in this area.

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Section: Translationalmentioning

confidence: 98%

Scoping review: hotspots for COVID-19 urological research: what is being published and from where?

Perera

Lawrentschuk

et al. 2020

World J Urol

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“…Androgen Receptor (AR, ρ = 0.57, FDR = 8.8E-04, rank 13), is the receptor for the male hormone androgen, plays a major role in reproductive system development, somatic differentiation, and behavior (Matsumoto, Shiina, Kawano, Sato, & Kato, 2008). Androgen-AR signaling induces ACE2 (Wu et al, 2020), while knockdowns of AR result in downregulation of ACE2 (Samuel et al, 2020). AR agonists also reduce SARS-CoV-2 spike protein-mediated cellular entry (Deng, Rasool, Russell, Natesan, & Asangani, 2021).…”

Section: B Top Erc Interactions Link Ace2 To Covid Pathologiesmentioning

confidence: 99%

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

Cheng

Werren

2021

Preprint

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Angiotensin-converting enzyme 2 (ACE2) is the human cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken a different approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that "coevolve" with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact directly with ACE2, while additional predicted novel interactors with ACE2 are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as coagulation factor V and fibrinogen components FGG, FGB, and FGA, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). Additionally, ACE2 has connections to proteins involved in cytokine signaling and immune response (e.g. IFNAR2, XCR1, and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has also elucidated possible functions for previously uncharacterized proteins and possible additional functions for well-characterized ones. Suggested validation approaches for ERC predicted ACE2 interacting proteins are discussed. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

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“…TMPRSS2 is highly expressed in human prostate epithelial cells and its regulation by androgen, which may lead to prostate susceptible to SARS-CoV-2 infection, and may be a biological risk factor for males. In addition, it was also reported that the androgen receptor (AR) can bind to the gene transcription promoter sequences of ACE2 and TMPRSS2, and androgen-AR activation may induce the expression of ACE2 and TMPRSS2 [ 40 ]. Dihydrotestosterone (DHT, AR activator) induces the expression of ACE2 and TMPRSS2 in activin-sensitive prostate cancer cells (LNCaP) and A549 non-small cell lung cancer cells, and GT0918 (a new generation of AR antagonists) can inhibit DHT-induced expression of ACE2 and TMPRSS2 [ 40 ].…”

Section: Function and Distribution Of Ace2mentioning

confidence: 99%

“…In addition, it was also reported that the androgen receptor (AR) can bind to the gene transcription promoter sequences of ACE2 and TMPRSS2, and androgen-AR activation may induce the expression of ACE2 and TMPRSS2 [ 40 ]. Dihydrotestosterone (DHT, AR activator) induces the expression of ACE2 and TMPRSS2 in activin-sensitive prostate cancer cells (LNCaP) and A549 non-small cell lung cancer cells, and GT0918 (a new generation of AR antagonists) can inhibit DHT-induced expression of ACE2 and TMPRSS2 [ 40 ]. These results indicate that AR plays a role in controlling the expression of ACE2 and TMPRSS2.…”

Section: Function and Distribution Of Ace2mentioning

confidence: 99%

The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities

Pang

Zhang

et al. 2020

Molecules

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December 2019 saw the emergence of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has spread across the globe. The high infectivity and ongoing mortality of SARS-CoV-2 emphasize the demand of drug discovery. Angiotensin-converting enzyme II (ACE2) is the functional receptor for SARS-CoV-2 entry into host cells. ACE2 exists as a membrane-bound protein on major viral target pulmonary epithelial cells, and its peptidase domain (PD) interacts SARS-CoV-2 spike protein with higher affinity. Therefore, targeting ACE2 is an important pharmacological intervention for a SARS-CoV-2 infection. In this review, we described the two-way switch role of ACE2 in the treatment of novel coronavirus pneumonia and underlying comorbidities, and discussed the potential effect of the ACE inhibitor and angiotensin receptor blocker on a hypertension patient with the SARS-CoV-2 infection. In addition, we analyzed the S-protein-binding site on ACE2 and suggested that blocking hot spot-31 and hot spot-353 on ACE2 could be a therapeutic strategy for preventing the spread of SARS-CoV-2. Besides, the recombinant ACE2 protein could be another potential treatment option for SARS-CoV-2 induced acute severe lung failure. This review could provide beneficial information for the development of anti-SARS-CoV-2 agents via targeting ACE2 and the clinical usage of renin-angiotensin system (RAS) drugs for novel coronavirus pneumonia treatment.

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Suppression of Androgen Receptor (AR)-ACE2/TMPRSS2 Axis by AR Antagonists May Be Therapeutically Beneficial for Male COVID-19 Patients

Cited by 11 publications

References 16 publications

Scoping review: hotspots for COVID-19 urological research: what is being published and from where?

Scoping review: hotspots for COVID-19 urological research: what is being published and from where?

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities

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