Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for your work on this manuscript. The manuscript has significant room for improvement.

1. Abstract
   The abstract is too short and does not follow a clear structure (background, materials and methods, results, conclusions). In addition, it does not clearly explain why this review is important or provide a “hook” to motivate the reader to continue.
2. Introduction and figures
   Please remove the figures from the Introduction; it is not appropriate to include them there. Also, the Introduction does not clearly state the aim of the study, which should be explicitly formulated at the end of the section.
3. Scope of the Introduction (SGLT2i and GLP-1 agonists)
   In the Introduction you discuss SGLT2 inhibitors and GLP-1 receptor agonists. It is not entirely clear why these are included, since the main focus of the review is on ACE2 inhibitors in glomerular injury. A more appropriate main comparison would be between SARS-CoV-2–related and non–SARS-CoV-2–related glomerular injury, which would also represent an interesting research gap.
4. Language, spacing, and typographical errors
   The manuscript contains numerous spacing and typographical errors (for example, around lines 20, 22, 52, 60, 123, etc.). A thorough proofreading and language revision is needed.
5. Materials and Methods section
   There is no Materials and Methods section. Please describe how the literature search was performed, including databases used, search strategy, and predefined inclusion and exclusion criteria.
6. Literature matrix
   A literature matrix (summary table of the included studies) would be very helpful for readers, summarizing key study characteristics and main findings.
7. Structure and flow
   The text often feels “strung together,” without a clear logical flow. Consider restructuring the manuscript, improving transitions between sections, and avoiding repetition so that the argument develops in a more coherent and organized way.
8. Conclusion
   The conclusion is rather narrative, and the main message is not entirely clear. Please revise and proofread this section to make the key conclusions more concise, explicit, and directly linked to the objective of the review.

 

Comments on the Quality of English Language

The manuscript contains numerous typographical and grammatical errors.

Author Response

Comment 1: Abstract: The abstract is too short and does not follow a clear structure (background, materials and methods, results, conclusions). In addition, it does not clearly explain why this review is important or provide a “hook” to motivate the reader to continue.
Response 1: Thank you for pointing this out, we have added a brief overview of the effects of angiotensin II activity in the RAAS, and where ACE2 function fits in.
 
Comment 2: Please remove the figures from the Introduction; it is not appropriate to include them there. Also, the Introduction does not clearly state the aim of the study, which should be explicitly formulated at the end of the section.
Response 2: We have removed the first two figures, and replaced the figure representing the role of soluble ACE2 as a decoy receptor for the SARS-CoV-2 virus on page 10. Additionally, the introduction has been lengthened to better transition into the content of the manuscript.
 
Comment 3: In the Introduction you discuss SGLT2 inhibitors and GLP-1 receptor agonists. It is not entirely clear why these are included, since the main focus of the review is on ACE2 inhibitors in glomerular injury. A more appropriate main comparison would be between SARS-CoV-2–related and non–SARS-CoV-2–related glomerular injury, which would also represent an interesting research gap.
Response 3: Thank you for this, accordingly, the the content on SGLT2 inhibitors and GLP-1 agonists have been removed.
 
Comment 4: The manuscript contains numerous spacing and typographical errors (for example, around lines 20, 22, 52, 60, 123, etc.). A thorough proofreading and language revision is needed.
Response 4: A thorough review of the language, spacing, and grammar has been performed.
 
Comment 5: There is no Materials and Methods section. Please describe how the literature search was performed, including databases used, search strategy, and predefined inclusion and exclusion
criteria.
Response 5: We appreciate this feedback. We have included information on our search at the end of the Introduction. 

Comment 6: A literature matrix (summary table of the included studies) would be very helpful for readers, summarizing key study characteristics and main findings.
Response 6: Our intent was not to compare particular ACE2 studies, but rather summarize the recent literature on ACE2 as it pertains to glomerular injury and COVID-19 infection, as such we did not include a summary table of the included studies.
 
Comment 7: The text often feels “strung together,” without a clear logical flow. Consider restructuring the manuscript, improving transitions between sections, and avoiding repetition so that the argument develops in a more coherent and organized way.
Response 7: Thank you for this feedback, we have taken the time to revise the flow of the manuscript, even adding a new section starting on page 6 with the goal of increasing the clarity of Ang-1-7 function within the RAAS to fill in any gaps.
 
Comment 8: The conclusion is rather narrative, and the main message is not entirely clear. Please revise and proofread this section to make the key conclusions more concise, explicit, and directly linked to the objective of the review.
Response 8: In accordance with your feedback, the conclusion has been modified to contain a more relevant summary of the main points emphasized in out manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presents a comprehensive overview of the renin–angiotensin–aldosterone system (RAAS) with emphasis on the enzymatic and receptor roles of ACE2 in glomerular injury and SARS-CoV-2 infection, offering solid educational value but limited novelty. The review effectively summarizes classical and modern aspects of RAAS but lacks mechanistic depth regarding ACE2-regulated intracellular signaling, oxidative stress, and fibrogenic pathways, and should better integrate recent omics and clinical findings after 2023. For example, to improve novelty, the authors should integrate recent omics-based insights (e.g., single-cell RNA-seq datasets showing cell-specific ACE2–TMPRSS2 co-expression patterns in diabetic nephropathy and COVID-19 kidneys) and highlight unresolved mechanistic questions, such as the signaling interplay between Ang-(1–7)/Mas and AT1R under inflammatory stress. Figure5 is clear but overly simplistic: Figure 5 should depict the pharmacokinetic limitations of soluble ACE2 therapy. Minor revisions include correcting typographical errors and standardizing abbreviations. Overall, this is a well-structured but descriptive review that requires mechanistic integration, updated references, and improved figure synthesis before acceptance.

 

Minor Comments

1. Replace redundant introductory details (lines 18–30) with a concise overview of RAAS focusing on its relevance to glomerular injury
2. Correct typographical issues (e.g., “maintencece” → “maintenance”) and inconsistent figure labeling (e.g., “BioRender.Com” → “BioRender.com”).
3. Abbreviations such as “Ang-(1–7)” and “COVAN” should be defined at first mention and used consistently thereafter.

Author Response

Comment 1: The manuscript presents a comprehensive overview of the renin–angiotensin–aldosterone system (RAAS) with emphasis on the enzymatic and receptor roles of ACE2 in glomerular injury and SARS-CoV-2 infection, offering solid educational value but limited novelty. The review effectively summarizes classical and modern aspects of RAAS but lacks mechanistic depth regarding ACE2-regulated intracellular signaling, oxidative stress, and fibrogenic pathways, and should better integrate recent omics and clinical findings after 2023. For example, to improve novelty, the authors should integrate recent omics-based insights (e.g., single-cell RNA-seq datasets showing cell-specific ACE2–TMPRSS2 co-expression patterns in diabetic nephropathy and COVID-19 kidneys) and highlight unresolved mechanistic questions, such as the signaling interplay between Ang-(1–7)/Mas and AT1R under inflammatory stress. Figure5 is clear but overly simplistic: Figure 5 should depict the pharmacokinetic limitations of soluble ACE2 therapy. Minor revisions include correcting typographical errors and standardizing abbreviations. Overall, this is a well-structured but descriptive review that requires mechanistic integration, updated references, and improved figure synthesis before acceptance.
Response 1: Thank you for this feedback on our manuscript. There has been limited RNA-seq data on ACE2-TMPRSS2 co-expression, however we have included details on locations within the kidney with increased ACE2 expression on page 4, within section 4. As for figure 5, we have replaced this figure with one from another published study which better represents the role of soluble ACE2. This can be seen on page 10, as figure 3. 

Comment 2: Replace redundant introductory details (lines 18–30) with a concise overview of RAAS focusing on its relevance to glomerular injury
Response 2: Thank you, this change has been made, with the introduction being revised to be more focused on the primary contents of the manuscript. 

Comment 3: Correct typographical issues (e.g., “maintencece” → “maintenance”) and inconsistent figure labeling (e.g., “BioRender.Com” → “BioRender.com”).
Response 3: A thorough review of grammar and spelling has been conducted to correct these errors.

Comment 4: Abbreviations such as “Ang-(1–7)” and “COVAN” should be defined at first mention and used consistently thereafter.
Response 4: We appreciate this note. All abbreviations have now been defined at first use.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

This manuscript provides a detailed overview of the renin–angiotensin–aldosterone system (RAAS) and its related molecule ACE2, outlining important pathophysiological mechanisms in kidney disease and cardiovascular disorders. In particular, the comparison between the classical RAAS pathway and the non-classical RAAS pathway (ACE2/Ang(1–7)/Mas receptor axis), with an emphasis on the protective role of ACE2, is clear and useful for readers.

However, the following points warrant improvement:

Depth of molecular mechanisms: While the review presents an overall picture of RAAS, the specific molecular signals underlying RAAS activation in chronic kidney disease (CKD) and the mechanisms by which ACE2 suppresses disease progression remain somewhat superficial. Incorporating recent findings and providing a more in-depth explanation of the molecular mechanisms would enhance the manuscript’s scientific impact.

Updating references: Some parts of the manuscript rely on older studies, and there is a lack of recent references, including relevant reviews. It is recommended to include up-to-date citations, especially regarding clinical applications and ACE2 as a therapeutic target.

Use of figures and tables: Given the complexity of RAAS pathways, including illustrative figures showing key molecular interactions and the characteristics of the local RAAS system within the kidney would improve readers’ understanding.

Emphasis on clinical significance: Further discussion on the effects of RAAS inhibitors and ACE2-related therapies on CKD management, supported by concrete clinical data and evidence, would increase the manuscript’s relevance and reader interest.

 

Author Response

Comment 1: Depth of molecular mechanisms: While the review presents an overall picture of RAAS, the specific molecular signals underlying RAAS activation in chronic kidney disease (CKD) and the mechanisms by which ACE2 suppresses disease progression remain somewhat superficial. Incorporating recent findings and providing a more in-depth explanation of the molecular mechanisms would enhance the manuscript’s scientific impact.
Response 1: Thank you for this comment. To adjust, we have added a new section "5. The Role of Ang-(1-7) in Protecting against Glomerular Injury" to take a deeper dive into the role of Ang-(1-7) in protecting glomerular function. 

Comment 2: Updating references: Some parts of the manuscript rely on older studies, and there is a lack of recent references, including relevant reviews. It is recommended to include up-to-date citations, especially regarding clinical applications and ACE2 as a therapeutic target.
Response 2: Thank you for this feedback. The older studies were used to help outline the foundational work that has been done in ACE2 research, however we have tried to keep their use to a minimum. We have added citations from work done within this calendar year, as can be seen in the references section.

Comment 3: Use of figures and tables: Given the complexity of RAAS pathways, including illustrative figures showing key molecular interactions and the characteristics of the local RAAS system within the kidney would improve readers’ understanding.
Response 3: We appreciate this comment. Our intent was to make the figures easy to follow while being good supplements for the reader to visualize the effects of RAAS activation and relation between SARS-CoV-2 and ACE2. 

Comment 4: Emphasis on clinical significance: Further discussion on the effects of RAAS inhibitors and ACE2-related therapies on CKD management, supported by concrete clinical data and evidence, would increase the manuscript’s relevance and reader interest.
Response 4: Our primary focus was not the use of RAAS inhibitors. Despite their mention in some in vitro studies referenced, there is limited research on ACE2 specific agents in the clinical context. 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

In my opinion, this manuscript requires substantial revision before it can be considered a scientific review suitable for a journal such as IJMS. The text presents a large amount of information, but the scope and aims are not clearly defined. Much of the content reads as narrative description rather than a structured, critical review.

The abstract is not engaging and does not clearly communicate the purpose, novelty, main conclusions, and significance of the work. The introduction also needs major improvement, particularly in establishing a clear rationale, defining the review questions/objectives, and positioning the manuscript within current literature.

I noted that the introduction is 13 rows long, with three lines addressing methodology. What is the scope of the methodology in introduction section? 

For a review article, the methodology ( search strategy, inclusion/exclusion criteria, databases, time frame, and selection process) must be clearly described to ensure transparency and reproducibility.

Due to these issues, I did not proceed further, as the manuscript in its current form is too weak and lacks the structure and rigor expected for publication.

Comments on the Quality of English Language

The manuscript contains numerous typographical and grammatical errors.

Author Response

We are grateful to the reviewer for the comments. In accord with the suggestions, we have re-written the abstract to more clearly indicate our literature search strategy and to emphasize that the review focuses on ACE2 and glomerular injury as well as on the role of ACE2 as a cellular receptor for SARS-CoV-2. We have also revised the Introduction. The paragraph on CKD was deleted. The Introduction now starts with a description of the classical RAAS. 

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

I have reviewed your revision and must highlight several outstanding issues that require correction:

1. Abstract The abstract must be organized with four clearly labeled subsections: Background/Objectives, Materials and Methods, Results, and Conclusions. Additionally, please revise the abstract to be more engaging it should immediately convey the significance and novelty of your work.

2. Introduction - Citations Citation formatting is inconsistent ([1] [2] without proper punctuation). Please follow journal guidelines: [1,2] or [1, 2] with appropriate spacing.

3. Introduction - Study Aims Include a clear, concise statement of study aims at the end of the Introduction (3-6 sentences). This is an internationally accepted standard that improves manuscript clarity.

4. Figures Please remove figures from the Introduction section, as previously requested.

5. Section Organization Ensure "Materials and Methods" appears as a distinct section heading.

6. Conclusions Please make the Conclusions more succinct and ensure they clearly address the study's key findings and implications.

7. Clinical Implications Adding a statement on clinical implications would significantly strengthen the manuscript.

Please take adequate time to address these issues thoroughly. These are essential requirements for publication, and the manuscript cannot be accepted until they are properly resolved.

Kind regards

Comments on the Quality of English Language

The manuscript contains numerous typographical and grammatical errors.

Author Response

Comment 1: Abstract The abstract must be organized with four clearly labeled subsections: Background/Objectives, Materials and Methods, Results, and Conclusions. Additionally, please revise the abstract to be more engaging it should immediately convey the significance and novelty of your work.

Response 1: As per editor feedback, the overall structure of the manuscript is appropriate for the journal, and the abstract reflects the key points that are focused on in the manuscript. 

 

Comment 2: Introduction - Citations Citation formatting is inconsistent ([1] [2] without proper punctuation). Please follow journal guidelines: [1,2] or [1, 2] with appropriate spacing

Response 2: Thank you for pointing this out, it has been amended. 

 

Comment 3: Introduction - Study Aims Include a clear, concise statement of study aims at the end of the Introduction (3-6 sentences). This is an internationally accepted standard that improves manuscript clarity.

Response 3: A paragraph has been added to the end of the Introduction outlining the four aims of the manuscript. This can be found in lines 87-96. 

 

Comment 4:  Figures Please remove figures from the Introduction section, as previously requested.

Response 4: All figures and any mention of figures have been removed from the Introduction.

 

Comment 5: Section Organization Ensure "Materials and Methods" appears as a distinct section heading.

Response 5: As per feedback from the editor, the format of the manuscript has been remained unchanged.

 

Comment 6: Conclusions Please make the Conclusions more succinct and ensure they clearly address the study's key findings and implications.

Response 6: Thank you for this feedback. We have revies the conclusion to be more succinct, only including the important takeaways from the manuscript. 

 

Comment 7: Clinical Implications Adding a statement on clinical implications would significantly strengthen the manuscript.

Response 7: We have taken the time to add a new section dedicated to the clinical relevance of the major research presented in the manuscript. This can be found from lines 490-520. 

 

Round 4

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for submitting your revised manuscript. After reviewing the revision, I still have several substantive and presentation issues that need to be addressed before the manuscript can be considered for publication.

1. Methodology / search strategy

• In the abstract you state that you conducted searches in Google Scholar and PubMed; however, the manuscript does not include a Methodology/Methods section describing how the literature search was performed.

• Please add a dedicated Methods section detailing (at minimum): databases searched, search terms/strings, date range, inclusion/exclusion criteria, screening process, and how evidence was synthesized. Without this, the review is not reproducible.

2. Abstract

• The abstract currently lacks an appropriate structure and does not clearly present a conclusion.

• Please revise to a structured abstract (e.g., Background/Aim, Methods, Results/Key Findings, Conclusion). The conclusion should explicitly state the main take-home message(s) supported by the review.

3. Abbreviations

• The abbreviation RAAS should be defined at first use in the Introduction (I did not see this in the current version). Please ensure all abbreviations are introduced consistently.

4. Introduction: missing context aligned with the title

• Given the title, the Introduction should include a concise definition/overview of SARS-CoV-2 and the impact on the RAS/RAAS axis, including relevant discussion of ACE inhibitors, angiotensin II, ACE2, and related mechanisms.

• At present, this content is either missing or insufficiently developed relative to what the title promises.

5. Referencing and paragraph structure

• Lines 26–37: This passage contains claims without references, and the paragraph is excessively long. Please (a) add appropriate citations and (b) split into shorter, logically organized paragraphs.

• Line 50: A reference is required for the stated claim.

6. Figures and citation consistency

• Figure 1: Please correct the placement and formatting of the figure citation so that it conforms to journal style (typically cited in the text at the appropriate point and presented with caption placement consistent with the journal’s requirements; currently the citation placement appears incorrect).

• Figure 2: There is an inconsistency between the figure citation and the references cited in the text (the figure appears to credit one author while the text cites two sources). Please reconcile this so that attribution and citations are consistent.

7. Author contributions

• The contributor listed as “X.X.” is unclear. Please replace with the correct author initials/name as required by the journal.

8. Text clarity

• Line ~500: The meaning of this line is unclear. Please revise for clarity and correct grammar/wording.

9. Clinical implications

• The Clinical Implications section would be strengthened by adding quantitative context where possible, for example: the extent to which RAAS modulation reduces progression of glomerulosclerosis, and discussion of relevant adverse effects/limitations, supported by citations.

• Please also proofread this section carefully.

Overall, the manuscript requires additional methodological transparency, restructuring of the abstract, strengthening of the introduction to align with the title, and careful correction of citation/figure attribution and language issues.

Comments on the Quality of English Language

The manuscript contains numerous typographical and grammatical errors