Most Arginase-1 Positive Cells Are Likely Injured S3 Proximal Tubular Cells Carrying Upregulated Phagocytotic Capacity rather than M2 Macrophages—Too Many To Be True

Shin et al.¹ recently published a very interesting study demonstrating mice with selective knockout arginase-1 (Arg1^mko) in myelomonocytic cells had decreased tubular repair and decreased survival after ischemia-reperfusion injury (IRI). Control mice (Arg1^con) showed extensive arginase-1 expression in the medulla but Arg1^mko mice did not (figures 1E, left panels, and 4A in Shin et al.¹). The researchers concluded that arginase-1–rich macrophages (M2) were required for the S3 tubular cell repair after IRI. However, when we looked at the histology of renal sections from both Arg1^con and Arg1^mko in figure 2D (right enlarged panels), the main cells forming tubular configurations were S3 proximal tubular epithelial cells in both types of mice, similar to what we have demonstrated in the rat model of IRI.² It is not possible for there to be so many arginase-1–positive macrophages (M2) in figure 2D (right enlarged panels) to correspond to the starry-sky amount of arginase-1 expression shown in both figure 1E (Arg1^con, left panel) and figure 4A. In addition, their F4/80 (an M1 macrophage marker) staining was also extensively positive in both Arg1^con and Arg1^mko of figure 1E (left panels). There appear to be too many F4/80-staining cells for these cells to be true macrophages after IRI on the basis of the histology images of figure 2D (right enlarged panels).

We think that most arginase-1–positive cells after IRI were likely from injured S3 proximal tubules. We suggest the authors can easily confirm our speculation by double restaining the kidney sections using arginase-1 and PAX-8 (a nuclear marker for renal tubules). We hypothesize the extensive positive F4/80 staining in figure 1E was most likely positive in the injured S3 proximal tubules of both types of mice. Injured proximal tubules are well known to have a phagocytic capacity, with upregulated kidney injury molecule-1 acting as receptors that prevent activation of inflammation.^3,4 Higher expression of kidney injury molecule-1 in the injured proximal tubules is associated with better recovered renal function.^5,6 In addition, the injured proximal tubules are positive for lysosome marker CD68, confirming the phagocytic capability of injured proximal tubules (our unpublished data).

In summary, Shin et al.¹ have provided critical evidence of arginase-1 in renal tubular repair, but we suggest they clarify whether the multiple arginase-1–rich cells seen after IRI are injured S3 proximal tubular cells or M2 macrophages. Further studies may pave the way for understanding how arginase-1 interacts with some repairing molecules, including GM-CSF, in injured proximal tubules.

Disclosures

N.B. Blatt reports having ownership interest in Lycera (ownership interest ended November 2021). All remaining authors have nothing to disclose.

Funding

None.

Author Contributions

N.B. Blatt, H.D. Kanaan, and L.T. Wickman reviewed and edited the manuscript; N.B. Blatt, H.D. Kanaan, and P.L. Zhang were responsible for formal analysis; and P.L. Zhang conceptualized the study and wrote the original draft.