The Pathophysiological Basis of Diabetic Kidney Protection by Inhibition of SGLT2 and SGLT1
Round 1
Reviewer 1 Report
In this review, Oe and Vallon provide an overview of the pleiotropic effects of SGLT2 inhibition that mediates kidney protection. The review is well written and I enjoyed reading it.
I only have a couple of minor comments.
- Please define every acronym before its first use.
- Abstract: I would suggest amending the first sentence as follows: “SGLT2 inhibitors can protect the kidneys of patients with and without type 2 diabetes mellitus and slow the progression towards end stage kidney disease”.
- Abstract, line 16: plase change “SGLT2 inhibitors counter hyperreabsorption” with “SGLT2 inhibitors counteract hyperreabsorption”.
- Page 5, line 215: please change “CKD level 2/3” to “CKD stage 2/3”.
- Page 6, line 250: please change “STZ-diabetic mice” with “Streptozocin-induced (STZ) diabetic mice”.
- Page 7, line 334-338: “Empagliflozin reduced the renal accumulation of p62, an indicator of autophagy activity, suggesting the improvement of autophagy in the diabetic kidney of Akita mice [33]. In vitro, empagliflozin and dapagliflozin inhibited mTOR in renal tubular cells under high glucose condition and increased autophagic activity, which resulted in improved mitochondrial biogenesis [118,119]” please rephrase and clarify because it seems that SGLT2 inhibition reduces and enhances autophagy at the same time.
- Page 10, line 454-456: “As a consequence, pharmacological inhibition of SGLT1 attenuated the high glucose-induced attenuation of TGF-induced afferent arteriolar constriction in the isolated perfused juxtaglomerular apparatus [14]” please rephrase.
- Page 10, line 456-459: “Moreover, the absence of SGLT1 prevented the Akita diabetes-induced upregulation in MD-NOS1 expression and attenuated the inhibition of TGF in Akita mice [13,168], and attenuated glomerular hyperfiltration in Akita and STZ-diabetic mice [13]”, please rephrase.
Author Response
The following are specific responses to the comments of Reviewer 1:
Reviewer 1:
In this review, Oe and Vallon provide an overview of the pleiotropic effects of SGLT2 inhibition that mediates kidney protection. The review is well written and I enjoyed reading it.
Response: Thanks.
I only have a couple of minor comments.
Please define every acronym before its first use.
Response: we reviewed the manuscript accordingly.
Abstract: I would suggest amending the first sentence as follows: “SGLT2 inhibitors can protect the kidneys of patients with and without type 2 diabetes mellitus and slow the progression towards end stage kidney disease”.
Response: Done.
Abstract, line 16: plase change “SGLT2 inhibitors counter hyperreabsorption” with “SGLT2 inhibitors counteract hyperreabsorption”.
Response: Done.
Page 5, line 215: please change “CKD level 2/3” to “CKD stage 2/3”.
Response: Done.
Page 6, line 250: please change “STZ-diabetic mice” with “Streptozocin-induced (STZ) diabetic mice”.
Response: Done.
Page 7, line 334-338: “Empagliflozin reduced the renal accumulation of p62, an indicator of autophagy activity, suggesting the improvement of autophagy in the diabetic kidney of Akita mice [33]. In vitro, empagliflozin and dapagliflozin inhibited mTOR in renal tubular cells under high glucose condition and increased autophagic activity, which resulted in improved mitochondrial biogenesis [118,119]” please rephrase and clarify because it seems that SGLT2 inhibition reduces and enhances autophagy at the same time.
Response: Done.
Page 10, line 454-456: “As a consequence, pharmacological inhibition of SGLT1 attenuated the high glucose-induced attenuation of TGF-induced afferent arteriolar constriction in the isolated perfused juxtaglomerular apparatus [14]” please rephrase.
Response: Done.
Page 10, line 456-459: “Moreover, the absence of SGLT1 prevented the Akita diabetes-induced upregulation in MD-NOS1 expression and attenuated the inhibition of TGF in Akita mice [13,168], and attenuated glomerular hyperfiltration in Akita and STZ-diabetic mice [13]”, please rephrase.
Response: Done.
Reviewer 2 Report
This is a nice paper. However, I have some comments. The findings from this paper are excellent and worthy to review. This manuscript contained some questions described below. I think this paper is interesting, this review contributes to future's clinical medicine largely. I have some questions from a point of view of clinical medicine.
SGLT2 inhibition is expected to have multiple effects such as blood glucose control, renal protection, and improvement of anemia. Furthermore, a joint effect with SGLT1 is expected, but it has not been established yet. One of the reasons is that the degree of inhibition of SGLT1 / 2 is different. Since it may be used as a comparison between several types of SGLT2 inhibitors on the market, how can the multifaceted effect depending on the degree of inhibition of SGLT1 / 2 change? I want you to tell me.
Author Response
The following are specific responses to the comments of Reviewer 2:
Reviewer 2:
This is a nice paper. However, I have some comments. The findings from this paper are excellent and worthy to review. This manuscript contained some questions described below. I think this paper is interesting, this review contributes to future's clinical medicine largely. I have some questions from a point of view of clinical medicine.
SGLT2 inhibition is expected to have multiple effects such as blood glucose control, renal protection, and improvement of anemia. Furthermore, a joint effect with SGLT1 is expected, but it has not been established yet. One of the reasons is that the degree of inhibition of SGLT1 / 2 is different. Since it may be used as a comparison between several types of SGLT2 inhibitors on the market, how can the multifaceted effect depending on the degree of inhibition of SGLT1 / 2 change? I want you to tell me.
Response to reviewer: The SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin, which have been used for the major outcome studies, vary to some extend in their selectivity for SGLT2 versus SGLT1 but they are still considered relative specific SGLT2 inhibitors. And the clinical studies to my understanding do not provide evidence for relevant differences in relevant outcomes. It will be important to take a close look at compounds that have a stronger effect on SGLT1 at therapeutic doses, such as sotagliflozin, or compounds with a selective effect on SGLT1 to better understand the clinical relevance of SGLT1 inhibition.
Round 2
Reviewer 2 Report
Regarding the answer from the author to me, if possible, please include the answer in the body of the paper.
Author Response
the answer has been included in text/conclusion section.
Round 3
Reviewer 2 Report
The manuscript was improved. I think that this paper may be suitable for publication to this journal in this revised manuscript. I have no specific comments.
