Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney
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Abstract
Aims
Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)—the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported.
Methods and results
We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis.
Conclusion
Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
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SciScore for 10.1101/2020.05.19.20106781: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Bioethics: The human studies adhered to the Declaration of Helsinki and were approved/ratified by the appropriate Bioethics Committee of the Medical University of Silesia (Katowice, Poland), Bioethics Committee of Karol Marcinkowski Medical University (Poznan, Poland), Ethics Committee of University of Leicester (Leicester, UK) and the University of Manchester Research Ethics Committee (Manchester, UK).
Consent: Informed written consents were obtained from all individuals – for the deceased donors from TRANSLATE-T, the consent was obtained from the members of the family.
IACUC: All animal experiments were approved by the University of Melbourne Animal …SciScore for 10.1101/2020.05.19.20106781: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Bioethics: The human studies adhered to the Declaration of Helsinki and were approved/ratified by the appropriate Bioethics Committee of the Medical University of Silesia (Katowice, Poland), Bioethics Committee of Karol Marcinkowski Medical University (Poznan, Poland), Ethics Committee of University of Leicester (Leicester, UK) and the University of Manchester Research Ethics Committee (Manchester, UK).
Consent: Informed written consents were obtained from all individuals – for the deceased donors from TRANSLATE-T, the consent was obtained from the members of the family.
IACUC: All animal experiments were approved by the University of Melbourne Animal Ethics Committee and were conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Kidney expression of ACE2 in rats treated with perindopril and losartan: To examine ACE2 expression in response to losartan and perindopril, we first sourced 6-week old inbred male spontaneously hypertensive rats (SHR) from the Animal Resources Centre (Canning Vale, Western Australia). Table 2: Resources
Software and Algorithms Sentences Resources We then used “--indep-pairwise” in PLINK to further prune variants in LD setting window size of 1000bp, step size of 50 variants and r2 cut-off threshold as 0.05. PLINKsuggested: (PLINK, RRID:SCR_001757)All sequenced samples were examined using several quality control filters including: number of total reads (>10million reads), D-statistic test (a normalised measure of within tissue sample inter-correlation, D≤5), sex compatibility check (consistency between the reported sex and expression of sex-specific genes, based on XIST and expression of RPS4Y1, KDM5D, DDX3Y, EIF1AY and USP9Y), verification of sample code based on comparing DNA base calls obtained from RNA-sequencing using GATK and DNA genotype calls and visual inspection of principal component plots of processed TPM data. GATKsuggested: (GATK, RRID:SCR_001876)Gene set overrepresentation for REACTOME pathways and gene ontology cellular compartment annotation was performed by the PANTHER classification system31 employing Fisher’s exact test. REACTOMEsuggested: (Reactome, RRID:SCR_003485)Official gene symbols for all ACE2 co-expressed genes were uploaded as an input list to the PANTHER analysis and were compared against all human genes. PANTHERsuggested: (PANTHER, RRID:SCR_004869)The kidney disease and BP gene sets were built from a combination of GWAS catalog (https://www.ebi.ac.uk/gwas/) association data for phenotypes “Blood pressure” (EF0_0004325) and “Kidney disease” (EF0_0003086) and manually curated genetic associations from the GWAS literature. https://www.ebi.ac.uk/gwas/suggested: (GWAS: Catalog of Published Genome-Wide Association Studies, RRID:SCR_012745)All models were adjusted for age, sex (as appropriate), BMI, sample ischaemic time, death classification on the Hardy scale30, 3 genetic PCs and a tissue-specific number of SVs inferred by the “sva” R package. Hardysuggested: (HARDY, RRID:SCR_009107)We then performed one-way ANOVA and unpaired student t-tests on ΔCt values using GraphPad Prism 8 to assess variability between groups and calculated fold change from ΔCt values equalling to 2-ΔΔCt with ΔΔCt = ΔCt(sample) – ΔCt(control). GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our analysis has an obvious limitation inherent to the observational origin of the detected associations. However, our findings are based on the largest available discovery dataset with >400 human kidneys and wherever feasible – replicated in independent resources. We also provide data from other human organs as context to our findings and make use of both whole tissue transcriptome profiling and single-cell experiments. In summary, we reveal findings of potential biological and epidemiological importance to the SARS-CoV-2 infection, i.e. the signature of age of ACE2 expression in tissues of relevance to COVID-19 and the lack of association between common cardiovascular and metabolic comorbidities of COVID-19 (i.e. hypertension, diabetes) on the renal expression of the SARS-CoV-2 entry receptor. Furthermore, the lack of association between renal expression of ACE2 and RAS blockers demonstrated in this study provides an important molecular argument in favour of safety of commonly prescribed BP lowering medications (RAS blockers) in patients with COVID-19. Finally, our data suggest that in the absence of SARS-CoV-2, renal ACE2 is positively associated with eGFR and lends support to the notion that renal ACE2 plays a more significant role in the local control of proximal tubule metabolism and kidney function rather than in systemic BP regulation50.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
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