Suppression of Indoxyl Sulfate Accumulation Reduces Renal Fibrosis in Sulfotransferase 1a1-Deficient Mice
, Hirofumi Jono 1,2, Yutaka Kakizoe 3, Yuichiro Izumi 3, Takashige Kuwabara 3, Masashi Mukoyama 3 and Hideyuki Saito 1,2,*
Eng Tat Ang
Round 1
Reviewer 1 Report
Interesting study with the animals.
The scientific content is of very good standard.
Clinically, I will be very interested to know if chronic kidney inflammation and fibrosis would cause it to shrink though. Can you comment on this?
The UUO model was interesting but I wonder if bilateral involvement of the ureters will change the outcome? can you comment on this too.
Overall, the manuscript has been well written and presented.
Author Response
Please see the attachment
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The article is valuable for its attempt to analyze an endogenous toxin that worsen the progression of CKD and for its design aiming at discovering the damaging mechanism. However, some improvements are needed.
It would be helpful, at beginning of the “Materials and Methods” section or of the “Result” section, to summarize the different steps of the experiment conducted to give the reader a general scheme in which the subsequent detailed description could be collocated. This would make it easier to follow the subsequent analysis
In the article there is not the reverse experiment: as Sult1a1 is involved in different processes, not only in the production of IS, to demonstrate that IS is the trigger of renal fibrosis it would be advisable to have a group of KO-mice in which it is administer in order to evaluate if the renal fibrosis and inflammation is restored. Is this experiment conducted and not described in the article? Is this experiment excluded for any reasons? Please explain or add it.
Did the authors consider to measure anti-fibrotic cytokines/markers?
An important consideration is that the proposed model as well as the others mentioned in the article (cisplatin toxicity and ischemia-reperfusion injury) are mainly pattern of tubular-interstitial injury, not of a glomerular one: could this affect the importance of the IS effect in these models?
Please explain what is FA/80 in 2.4 section.
Figure 1: A and B are inverted in the caption, E is not explained in the caption.
Figure 5 caption: line 149 misspelling of sfrp5
In almost all graphs in figure 1, 2, 3 and 4 there is a comparison between WT-UUO and Sult1a1-KO sham, this comparison is not explained in the text and it could be incorrect to compare these two groups: please explain the reason of the comparison or amend the graphs.
In figures 3, 4 and 6 the microscopic images are too small. In figure three and six the viewer has a general impression of the amount of the red staining but renal structures (such as glomeruli, tubules, vessels and interstitium) are hardly recognizable probably due to the reduced dimensions. In figure 4 it is almost impossible to distinguish also the differences between the four microscopic panels (figure 4C and 4D). As the presence of differences in staining is described in the result section, it would be advisable to improve both the dimension and the resolution of the microscopic images that needed to be of high quality.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
I thank the authors for the revised version of their manuscript. They addressed all the major concerns.
