Early Neural Changes as Underlying Pathophysiological Mechanism in Diabetic Retinopathy

Round 1

Reviewer 1 Report

The present review is written to focus on neural alterations in the diabetic retina at the early stage of diabetic retinopathy. The topic is important, and the text is generally well written. I have only a few minor comments.

L95, “BRB breakdown induces the formation of microaneurysms”. Is this description correct?

If correct, please an explanation of how BRB breakdown forms microaneurysms.

Fig. 1 “Protein Kinasa C activation”; Please correct “Kinasa” to “Kinase”

In Fig. 1, five events are listed as metabolic abnormalities. The figure makes an impression that AGEs toxicity initially occurs and then polyol pathway is activated. Subsequently, the increased activity of hexosamine pathway occurs and PKC is activated. I think that the order in which these events occur is unclear. Some happen at the same time. If so, please modify to avoid misunderstandings.

Author Response

Dear Editor,

We would like to thank the reviewers for the positive comments about our manuscript and for giving us the opportunity to submit a revised version. We have modified the manuscript to accommodate the reviewers’ comments. Please find below a detailed response to the reviewer’s comments as well as the changes that we have made in the manuscript.

Reviewer #1

The present review is written to focus on neural alterations in the diabetic retina at the early stage of diabetic retinopathy. The topic is important, and the text is generally well written. I have only a few minor comments.

ANSWER: We thank the reviewer for emphasizing the relevance of the topic in our manuscript and for pointing out that the manuscript is well-written.

L95, “BRB breakdown induces the formation of microaneurysms”. Is this description correct? If correct, please an explanation of how BRB breakdown forms microaneurysms.

ANSWER: The description is correct, as indicated in references #15-17 (doi:10.1007/s00125-017-4435-8; doi:10.1007/s10787-019-00647-9; doi:10.1016/j.pathophys.2017.07.001) . Information about the BRB breakdown is now provided, as suggested by the reviewer (lines 92 to 103)

Fig. 1 “Protein Kinasa C activation”; Please correct “Kinasa” to “Kinase”

ANSWER: The term “kinase” is now included in figure 1. We apologize for the misspelling.

In Fig. 1, five events are listed as metabolic abnormalities. The figure makes an impression that AGEs toxicity initially occurs and then polyol pathway is activated. Subsequently, the increased activity of hexosamine pathway occurs and PKC is activated. I think that the order in which these events occur is unclear. Some happen at the same time. If so, please modify to avoid misunderstandings.

ANSWER: In order to avoid a misinterpretation, we have made changes to the figure. We have also emphasized in the figure legend that the molecular events can occur simultaneously and the order in the list does not represent a chronological order (lines 539 to 542).

Author Response File: Author Response.pdf

Reviewer 2 Report

Canto et. Al. created excellent work regarding their argument that diabetic retinopathy should be approached from a neuro-apoptotic viewpoint in the next generation of diabetic retinopathy theapies. However, there was a major therapy in the treatment of DR that was not well-addressed: stem cells.
Stem cell therapy is an extremely important generation of therapy that deserved to be addressed in the paper, both from the actual locally targeted retinal stem cell treatment as well as the recruitment of stem cells from the bone marrow to the retina. Also, the authors should characterize, with more depth, the inflammatory intra-ocular environment in the pathogenesis / proliferation of DR, and how this is regulated by the systemic inflammatory system. The descriptions of the animal models used for DR should include the pathologic mechanisms as well as the limitations. Furthermore, there are some minor revisions that need to be addressed. The authors stated that DR is more common in pregnancy and puberty without a citation. With these additional corrections, this review written Canto et. Al. will make an excellent addition to the Internation Journall of Translational Medicine. 

Author Response

Dear Editor,

We would like to thank the reviewers for the positive comments about our manuscript and for giving us the opportunity to submit a revised version. We have modified the manuscript to accommodate the reviewers’ comments. Please find below a detailed response to the reviewer’s comments as well as the changes that we have made in the manuscript.

Reviewer#2

Canto et. Al. created excellent work regarding their argument that diabetic retinopathy should be approached from a neuro-apoptotic viewpoint in the next generation of diabetic retinopathy theapies. However, there was a major therapy in the treatment of DR that was not well-addressed: stem cells.

Stem cell therapy is an extremely important generation of therapy that deserved to be addressed in the paper, both from the actual locally targeted retinal stem cell treatment as well as the recruitment of stem cells from the bone marrow to the retina. Also, the authors should characterize, with more depth, the inflammatory intra-ocular environment in the pathogenesis / proliferation of DR, and how this is regulated by the systemic inflammatory system. The descriptions of the animal models used for DR should include the pathologic mechanisms as well as the limitations. Furthermore, there are some minor revisions that need to be addressed. The authors stated that DR is more common in pregnancy and puberty without a citation. With these additional corrections, this review written Canto et. Al. will make an excellent addition to the Internation Journall of Translational Medicine.

ANSWER: We thank the reviewer for emphasizing that the neuro-apoptotic viewpoint should be taken into consideration for the next generation of DR therapies.

As requested by the reviewer, we have now included information about the potential of Stem Cell therapy to fight against DR (from line 487 to508)

We have now included a paragraph that elaborates on the information regarding the inflammatory intra-ocular environment in the pathogenesis / proliferation of DR, as suggested by the reviewer (lines 128 to 139).

We have now included a paragraph describing the limitations and pathologic mechanisms associated with DR (lines 356 to 387).

We have now included a citation to support that DR is more common in pregnancy and puberty (PMID: 20580421) (line 49)

Author Response File: Author Response.pdf