Review Reports - The Lung–Kidney Axis: A Coordinated Regulation of Oxygen Sensing and Erythropoiesis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Overview

The paper systematically reviews the regulatory role of the lung-kidney axis in oxygen sensing and EPO production, further expanding on traditional knowledge. However, the article's innovation and research significance are not prominent, as only one author completed the literature collection, which carries a high likelihood of subjectivity and selection bias. The article's structure and logic are insufficient, and the image descriptions are inappropriate. Extensive revisions are needed.

Details

If there is only one author for a review, could it lead to selection bias and subjectivity during the article collection process? We believe the author should clearly indicate their contributions and specify what efforts have been made to avoid the above issues. At the beginning, the author mentioned using keyword searches and literature screening, but this kind of screening work is generally conducted by two or more independent researchers, and if the two are inconsistent, a third person is involved. So how did the author manage to do it alone?
Figure 1 seems to be explainable with text alone. Is it necessary to include a diagram for this part? If yes, the image may need more elaboration; if not, please remove it.
On page 6, lines 236-237 of the article, there is a description of Fig (2), but there is no image. This part requires the author to provide an explanation and make corrections.
The paragraph structure of the article needs to be clarified again, and hierarchical numbers such as 1., 1.1, 1.1.1, etc., need to be marked to distinguish the structure and logic of the article.
Most of the paragraphs in the article are too long, and some sections even exceed a whole page. For readers to better understand the content, should some readability changes be made? We believe that the author needs to consult professionals for the writing part of the article, as the current readability of the article is very poor.
As a small suggestion, we think that to facilitate readers' understanding, a diagram illustrating the operation of the Lung–Kidney Axis could be drawn at the beginning. This diagram should more completely convey the full meaning of the section "An Overview of the Lung–Kidney Axis in Systemic Homeostasis" than Figure 1.
The author mentioned multiple key factors and signaling pathways in the study that affect the entire research, but almost none of them are mentioned in the diagram. We believe the author should carefully consider adding the impact of signaling pathways, key factors, and even some main mechanisms on the study, and try to create a diagram.
The description of the article's innovative points is insufficient. The entire review mainly further improves traditional knowledge. Findings that are not present in traditional knowledge should be highlighted more as innovations; otherwise, the research significance of the article is not substantial.

Author Response

Respected Editor ’and Esteemed Reviewers,

I would like to take this opportunity to thank and sincerely appreciate the time and effort dedicated in reviewing and refining the manuscript. Your insightful comments, constructive suggestions, and meticulous attention to detail will significantly enhance the quality of the work. Respective answers to the reviewer’s comments have been included in the manuscript and highlighted.

Reviewer-1

Overview

Author Response to the overview

We sincerely thank the reviewer for the careful evaluation of our manuscript and for the constructive comments. All concerns have been carefully addressed, and the manuscript has been revised accordingly. We believe these revisions have significantly improved the scientific rigor, clarity, and overall impact of the work. We are grateful for the reviewer’s insightful feedback, which has greatly contributed to strengthening the manuscript. In response, we have enhanced the presentation of the manuscript’s novelty and scientific relevance by emphasizing the integrated lung–kidney axis framework, moving beyond the traditional view of isolated organ function. We have also incorporated recent evidence from major research databases to ensure the review reflects current advances in the field. Furthermore, the literature search strategy has been clarified in the Methods section, with explicit mention of the databases used, including PubMed, Scopus, and Web of Science. The manuscript has been reorganized into clearly defined thematic sections, guided by recent evidence, to improve logical flow, coherence, and alignment with the objectives of the present review.

Reviewer-1

Detail-1: -

If there is only one author for a review, could it lead to selection bias and subjectivity during the article collection process? We believe the author should clearly indicate their contributions and specify what efforts have been made to avoid the above issues. At the beginning, the author mentioned using keyword searches and literature screening, but this kind of screening work is generally conducted by two or more independent researchers, and if the two are inconsistent, a third person is involved. So how did the author manage to do it alone?

Author’s Reply

We thank the reviewers for their thoughtful comments. The review was conducted in a systematic manner using a structured approach, wherein relevant databases were searched (PubMed, Scopus and Web of Science) and sources were cross-checked wherever necessary to avoid bias. Ideally, a systematic review should be performed by independent reviewers; however, the present article is a narrative review. The literature was screened by a single individual, but in a structured fashion using a predefined search strategy and giving priority to high-quality studies, contemporary publications, and relevant review articles. The selected findings were cross-checked with relevant, high-impact articles and publications. The literature was selected based on relevance to the lung–kidney axis, oxygen sensing and erythropoietin regulation, using a set of predefined keywords, which are now provided in the Methods section of the revised article. Where evidence was unclear or conflicting, multiple supporting studies were examined to provide a balanced view of the data. Although a single author conducted the work, the individual possesses considerable subject expertise and long-standing research experience, and peer review has served to further validate the manuscript for originality, novelty, and accuracy. Please see the below updated MS.

1.1 Literature Selection Criteria

A comprehensive, web-based literature includes systematically examined major scientific databases which included PubMed, Scopus and Web of Science to find relevant research studies about renal-respiratory crosstalk with regards to erythropoiesis and oxygen homeostasis. The search-spanned databases cover studies published between 2004 and 2026. Keywords such as “erythropoiesis’” and the Medical Subject Headings (MeSH) term “lung kidney axis,” combined with “renin angiotensin aldosterone system,” as well as MeSH terms like “hypoxia-inducible factors,” “nitric oxide,” “renal oxygen extraction,” and “blood viscosity” in conjunction with “renal involvement,” iron involvement” AND “endothelial signaling pathways”, “microvascular shunting” AND “bone marrow”, and “perfusion oxygen delivery coupling were used to identify relevant studies.”

Detail-2:

Figure 1 seems to be explainable with text alone. Is it necessary to include a diagram for this part? If yes, the image may need more elaboration; if not, please remove it.

Author’s Reply

We thank the reviewer for this comment. Figure 1, In Section 1. Figure 1 is drawn into a better form. This figure serves as a clear and concise illustration of the major physiological functions controlled by the lung–kidney axis that contribute to systemic homeostasis. Please see below the MS is updated

An Overview of the Lung–Kidney Axis in Systemic Homeostasis

Lung kidney axis operates as a coordinated functional network regulating some of the vital functions of the body beyond acting as an autonomous organ system in maintaining homeostasis. The two systems interconnect through multiple regulatory domains, integrating pulmonary, renal and cardiovascular systems. This integration acts through various intricate neurohormonal and biochemical pathways. Central to this coordinated axis includes regulation of blood pressure and fluid balance control. Blood pressure regulation depends on the renin–angiotensin–aldosterone system (RAAS) and counter regulatory measure the ACE2/angiotensin-(1–7) system.¹ Together these regulatory system functions to govern vascular tone and sodium balance to keep blood pressure stable. Equally critical is the role of lung–kidney axis to maintain acid–base balance. The lungs maintain systemic pH acting immediately through their ability to eliminate carbon dioxide. While kidneys maintain long term pH stability by their role in tubular hydrogen excretion and bicarbonate reabsorption. This precise regulation maintains the pH in a steady state under variable metabolic and respiratory conditions.² In addition another important integrating aspect of lung-kidney axis is their involvement in fluid and electrolyte balance. The kidneys determine plasma composition through glomerular filtration and precise tubular reabsorption and secretion processes. Thereby maintaining systemic electrolyte homeostasis.¹⁰⁰ Pulmonary hemodynamics and vascular permeability govern the distribution of intravascular and interstitial fluid.¹⁰¹ The lungs enable insensible water loss through breathing. Epithelial sodium channel (ENaC) helps clear alveolar fluid through sodium transport followed by osmotic fluid drag from alveoli to blood stream or interstitium. The lungs generate osmotic gradients for maintaining alveolar dryness which enhances gas exchange through their controlled sodium and chloride transport system through ENaC and cystic fibrosis transmembrane conductance regulator (CFTR) channels. Further the lymphatic system removes excess fluid around alveoli and thus prevents pulmonary edema from developing. ^{3, 4} Arterial oxygen and tissue oxygen signifies additional key mechanism in the lung-kidney coordination. The lungs provide arterial oxygenation through gas exchange. While the kidneys produce EPO in response to renal blood flow variation and hypoxic signals. EPO stimulates erythropoiesis and raises the blood’s oxygen-carrying capacity.⁶⁷ The synchronized activities of these processes demonstrate that the lung-kidney system operates as an integrated interdependent physiological network maintaining homoeostasis by regulating vital fucntion.Fig-1 This present study aims to further elaborate and refines our understanding and uncovering the complex and dynamic interaction of this lung–kidney network. Predominantly emphasized on erythropoiesis, arterial oxygen balance and tissue oxygenation.

Figure 1. Crosstalk between Lungs and Kidneys in Homeostasis.

Detail-3

On page 6, lines 236-237 of the article, there is a description of Fig (2), but there is no image. This part requires the author to provide an explanation and make corrections.

Author’s Reply

We genuinely thank the reviewer for careful observation and for identifying this issue. We acknowledge that Figure 2 was not properly included or aligned with its corresponding description in the original manuscript. This has now been corrected in the revised version, with the figure appropriately inserted and it’s numbering accurately aligned with the relevant text.

Fig-3 Iron Metabolism in Erythropoiesis

Detail-4

The paragraph structure of the article needs to be clarified again, and hierarchical numbers such as 1., 1.1, 1.1.1, etc., need to be marked to distinguish the structure and logic of the article.

Author’s Reply

We would like to thank the reviewer for his thoughtful comments. Hierarchical numbering has been added to the manuscript to clearly distinguish between sections and subsections.

Detail-5

Most of the paragraphs in the article are too long, and some sections even exceed a whole page. For readers to better understand the content, should some readability changes be made? We believe that the author needs to consult professionals for the writing part of the article, as the current readability of the article is very poor.

Author’s Reply

We would like to thank the reviewer for his/her helpful comments. Some of the paragraphs were too long, because the many interactions in the system made it necessary to explain everything. To improve the manuscript, we have made the long paragraphs shorter. We have added subject specific subheadings to improve orientation and made the language and structure generally clearer, consistent and logical.

Detail-6

As a small suggestion, we think that to facilitate readers' understanding, a diagram illustrating the operation of the Lung–Kidney Axis could be drawn at the beginning. This diagram should more completely convey the full meaning of the section "An Overview of the Lung–Kidney Axis in Systemic Homeostasis" than Figure 1.

Author’s Reply

We thank the reviewer for this valuable suggestion. In response, we have added a new schematic diagram at the beginning of the section.

An Overview of the Lung–Kidney Axis in Systemic Homeostasis

Figure 1. Crosstalk between Lungs and Kidneys in Homeostasis.

Detail-7

The author mentioned multiple key factors and signaling pathways in the study that affect the entire research, but almost none of them are mentioned in the diagram. We believe the author should carefully consider adding the impact of signaling pathways, key factors, and even some main mechanisms on the study, and try to create a diagram.

Author’s Reply

We thank the reviewer for this insightful suggestion. We agree that the previous diagram did not fully reflect the complexity of the study. In response, we have carefully revised the figure to incorporate the major signaling pathways, key molecular factors, and principal mechanisms discussed in the manuscript. This updated diagram now provides a more comprehensive visual summary of the study and better aligns with the mechanistic depth of the text. In the updated MS, we have incorporated 6 figures to describe the relevant signaling pathways, key factors, and even some main mechanisms on the study.

Detail-8

The description of the article's innovative points is insufficient. The entire review mainly further improves traditional knowledge. Findings that are not present in traditional knowledge should be highlighted more as innovations; otherwise, the research significance of the article is not substantial.

Author’s reply

We would like to thank the reviewer for his comment regarding the clarity of the manuscript’s innovation and the importance of the study. We have revised the manuscript to emphasize the novelty of presenting the lung–kidney axis as an integrated systems approach. We have also updated the manuscript by adding new evidence from major research databases to illustrate updated mechanistic links between erythropoiesis and tissue oxygenation. These new and integrated insights into the field are explicitly shown in the new versions of three sections of the manuscript.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In this manuscript, the authors review the lung–kidney axis in the regulation of erythropoiesis and oxygen sensing. The topic is important and of broad interest; however, several concerns need to be addressed to improve clarity, accuracy, and scientific rigor.

Major concerns:

There is no figure that clearly illustrates the molecular mechanisms underlying the interaction between erythropoiesis and oxygen sensing or the role of the lung–kidney axis in this process. The two figures included in the current version provide limited informational value. A schematic summarizing key pathways and regulatory interactions would significantly improve the manuscript.
Many sentences are difficult to understand due to grammatical errors, run-on structures, sentence fragments, and unclear logical flow. These issues significantly affect readability.

Examples include:

Lines 509–511:
“The kidneys receive nearly 20–25% of cardiac output; even with this high cardiac output renal tissue show decrease renal oxygen extraction fraction (OEF) is less with low arterial venous oxygen difference.”
Lines 539–542:
“The kidneys obtain their blood supply from 20 to 25 percent of total cardiac output small decreases in cardiac output result in decreased renal blood flow and intrarenal oxygen delivery and hypoxia detection and erythropoietin synthesis.”
Lines 555–561:
(overly long and poorly structured sentence regarding oxygen consumption and HIF activation)

These are only a few examples; similar issues are present throughout the manuscript. Substantial language editing is required.

EPO production sources: The authors emphasize the role of the lung in producing “measurable levels of EPO.” However, it is well established that up to ~10% of EPO in adults is produced by the liver. This important physiological source should not be overlooked.
Role of the lung in hematopoiesis: The manuscript suggests that the lung serves as a reservoir for hematopoietic stem and progenitor cells (HSPCs), which may be misleading. In addition to the bone marrow, the spleen and liver are well-established hematopoietic sites, particularly during stress erythropoiesis. In contrast, the role of the lung in hematopoiesis is relatively limited and is primarily associated with platelet biogenesis. This distinction should be clarified.
HIF2α and intestinal iron absorption: In the discussion of HIF2α-regulated iron absorption, duodenal cytochrome b (Dcytb) should be included. Dcytb is transcriptionally upregulated by HIF2α and reduces ferric iron to ferrous iron, facilitating iron uptake via DMT1.
IRP1/IRP2 regulation of erythropoiesis and iron metabolism: IRP1 and IRP2 coordinately regulate erythropoiesis and iron availability. IRP1 has a higher affinity for the iron-responsive element (IRE) in HIF2α mRNA and therefore plays a prominent role in regulating EPO production. In contrast, IRP2 is critical for maintaining iron availability in erythroblasts to support hemoglobin synthesis. Additionally, IRP1 deficiency has been reported to induce endothelin-1 expression, leading to pulmonary hypertension, cardiac hypertrophy, and fibrosis. This suggests a potential role for IRP1 in the lung–kidney axis in regulating oxygen sensing and erythropoiesis, which should be discussed.
Lines 447–448: Endothelin-1 is also regulated by HIF2α and should be discussed in this context.
Insufficient citation of literature: Key statements and claims throughout the manuscript lack appropriate references. Citations should be provided immediately after statements presenting important evidence or conclusions.

Minor Comment

Missing figure, Lines 236–237: A figure legend is provided, but the corresponding figure is missing.

Comments on the Quality of English Language

Many sentences are difficult to understand due to grammatical errors, run-on structures, sentence fragments, and unclear logical flow. These issues significantly affect readability.

Examples include:

Lines 509–511:
“The kidneys receive nearly 20–25% of cardiac output; even with this high cardiac output renal tissue show decrease renal oxygen extraction fraction (OEF) is less with low arterial venous oxygen difference.”
Lines 539–542:
“The kidneys obtain their blood supply from 20 to 25 percent of total cardiac output small decreases in cardiac output result in decreased renal blood flow and intrarenal oxygen delivery and hypoxia detection and erythropoietin synthesis.”
Lines 555–561:
(overly long and poorly structured sentence regarding oxygen consumption and HIF activation)

These are only a few examples; similar issues are present throughout the manuscript. Substantial language editing is required.

Author Response

Reviewer-2

Comments and Suggestions for Authors

Author’s Reply

We would also like to thank the reviewer for his constructive comments on the clarity, accuracy and scientific completeness of our manuscript. We have revised the manuscript in detail and answered all the reviewer's comments point by point and incorporated the appropriate changes.

Major concern: -

Reviewer-2

Comment 1: - There is no figure that clearly illustrates the molecular mechanisms underlying the interaction between erythropoiesis and oxygen sensing or the role of the lung–kidney axis in this process. The two figures included in the current version provide limited informational value. A schematic summarizing key pathways and regulatory interactions would significantly improve the manuscript.

Author’s Reply

We thank the reviewer for this insightful suggestion. In response, we have carefully revised the figure to incorporate the major signaling pathways, key molecular factors, and principal mechanisms discussed in the manuscript. This updated diagram now provides a more comprehensive visual summary of the study and better aligns with the mechanistic depth of the text. In the updated MS, we have incorporated 6 figures to describe the relevant signaling pathways, key factors, and even some main mechanisms in the study.

Reviewer-2

Comment 2. Many sentences are difficult to understand due to grammatical errors, run-on structures, sentence fragments, and unclear logical flow. These issues significantly affect readability.

Examples include:

Lines 509–511:
“The kidneys receive nearly 20–25% of cardiac output; even with this high cardiac output renal tissue show decrease renal oxygen extraction fraction (OEF) is less with low arterial venous oxygen difference.”

Lines 539–542:
“The kidneys obtain their blood supply from 20 to 25 percent of total cardiac output small decreases in cardiac output result in decreased renal blood flow and intrarenal oxygen delivery and hypoxia detection and erythropoietin synthesis.”

Lines 555–561:
(overly long and poorly structured sentence regarding oxygen consumption and HIF activation)

These are only a few examples; similar issues are present throughout the manuscript. Substantial language editing is required.

Author’s Reply

We thank the reviewer for highlighting this important issue. In response, we have thoroughly revised the text, improving grammar, sentence structure, and logical flow throughout, to ensure greater clarity and readability.

We thank the reviewer for providing these specific examples, which were very helpful in identifying areas requiring improvement.

Lines 509–511: it is updated and can be found in the line number 579-582.
Lines 539–542: it is updated and can be found in the line number 621-649.
Lines 555–561: it is updated and can be found in the line number 628-637.

In addition to these specific corrections, we have performed comprehensive language editing throughout the manuscript to address similar issues and improve overall clarity and readability.

Reviewer-2

Comment 3. EPO production sources: The authors emphasize the role of the lung in producing “measurable levels of EPO.” However, it is well established that up to ~10% of EPO in adults is produced by the liver. This important physiological source should not be overlooked.

Author’s Reply

We thank the reviewer for this important clarification. We have revised the manuscript to explicitly include the role of the liver alongside the kidney and lung, ensuring a more accurate and comprehensive representation of EPO production sources. It can be found on the line 198-200

Reviewer-2

Comment 4. Role of the lung in hematopoiesis: The manuscript suggests that the lung serves as a reservoir for hematopoietic stem and progenitor cells (HSPCs), which may be misleading. In addition to the bone marrow, the spleen and liver are well-established hematopoietic sites, particularly during stress erythropoiesis. In contrast, the role of the lung in hematopoiesis is relatively limited and is primarily associated with platelet biogenesis. This distinction should be clarified.

Author’s reply

We thank the reviewer for this important clarification. Accordingly, we have revised the manuscript and have further supported this discussion with appropriate references. We have added following references in the updated MS.

Lefrancais E, Ortiz-Munoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM, Thornton EE, Headley MB, David T, Coughlin SR, et al. (2017). The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature, 544(7648), 105–109.
Borges I, Sena I, Azevedo P, Andreotti J, Almeida V, Paiva A, Santos G, Guerra D, Prazeres P, Mesquita LL, Silva LSB, Leonel C, Mintz A, Birbrair A. Lung as a Niche for Hematopoietic Progenitors. Stem Cell Rev Rep. 2017 Oct;13(5):567-574. doi: 10.1007/s12015-017-9747-z. PMID: 28669077; PMCID: PMC6093188.

Conrad C, Magnen M, Tsui J, Wismer H, Naser M, Venkataramani U, Samad B, Cleary SJ, Qiu L, Tian JJ, De Giovanni M, Mende N, Leavitt AD, Passegué E, Laurenti E, Combes AJ, Looney MR. Decoding functional hematopoietic progenitor cells in the adult human lung. Blood. 2025 May 1;145(18):1975-1986. doi: 10.1182/blood.2024027884. PMID: 40014797; PMCID: PMC7617544.

Reviewer-2

Comment 5. HIF2α and intestinal iron absorption: In the discussion of HIF2α-regulated iron absorption, duodenal cytochrome b (Dcytb) should be included. Dcytb is transcriptionally upregulated by HIF2α and reduces ferric iron to ferrous iron, facilitating iron uptake via DMT1.

Author’s Reply

We thank the reviewer for this valuable and insightful suggestion. We added following changes and these changes can be found in line 277-279

Reviewer-2

Comment 6. IRP1/IRP2 regulation of erythropoiesis and iron metabolism: IRP1 and IRP2 coordinately regulate erythropoiesis and iron availability. IRP1 has a higher affinity for the iron-responsive element (IRE) in HIF2α mRNA and therefore plays a prominent role in regulating EPO production. In contrast, IRP2 is critical for maintaining iron availability in erythroblasts to support hemoglobin synthesis. Additionally, IRP1 deficiency has been reported to induce endothelin-1 expression, leading to pulmonary hypertension, cardiac hypertrophy, and fibrosis. This suggests a potential role for IRP1 in the lung–kidney axis in regulating oxygen sensing and erythropoiesis, which should be discussed.

Author’s Reply

We thank the reviewer for this insightful and valuable comment. We added following changes and these changes can be found in line 300-308.

Reviewer-2

Comment 7: - Insufficient citation of literature: Key statements and claims throughout the manuscript lack appropriate references. Citations should be provided immediately after statements presenting important evidence or conclusions.

Author’s Reply

We thank the reviewer for highlighting this important issue. In response, we have carefully revised the manuscript to include appropriate and up-to-date citations. We can find them in updated MS, references from 99-175.

Reviewer-2

Minor comment

Missing figure, Lines 236–237: A figure legend is provided, but the corresponding figure is missing.

Author’s Reply

We thank the reviewer for this observation. We acknowledge that the figure was not visible in the original manuscript due to its placement on the final page. We have added new figures to accommodate the reviewer’s comments. It can be found in the page 8 of 27.

Reviewer-2

Comments on the Quality of English Language

Many sentences are difficult to understand due to grammatical errors, run-on structures, sentence fragments, and unclear logical flow. These issues significantly affect readability.

Examples include:

Lines 555–561:
(overly long and poorly structured sentence regarding oxygen consumption and HIF activation)

These are only a few examples; similar issues are present throughout the manuscript. Substantial language editing is required.

Author’s Reply

We thank the reviewer for providing these specific examples, which were very helpful in identifying areas requiring improvement.

Lines 509–511: it is updated and can be found in the line number 579-582.
Lines 539–542: it is updated and can be found in the line number 621-649.
Lines 555–561: it is updated and can be found in the line number 628-637.

In addition to these specific corrections, we have performed comprehensive language editing throughout the manuscript to address similar issues and improve overall clarity and readability.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author has made the necessary modifications to the research content, and we believe that there are no other comments requiring changes to the article at present. However, we would like to remind the editor that, in the process of explaining the first question from our previous review, the author also mentioned that this paper has only one author. We do not know whether this will create selection bias in publication. This part may need to be decided by the editorial team on whether to accept the paper.