Background: A recent study indicates that arginase-1 participates in M2 macrophage-mediated renal tubular regeneration in a rodent model (Shin et al. JASN 2022). As injured proximal tubule cells have a phagocytotic capacity (stain positively for CD68 and kidney injury moleucule-1 in previous studies), we hypothesized that the injured proximal tubules may stain positively for arginase1. Design: We analyzed PAS-stained renal biopsy sections for evidence of ATI using a semiquantitative scale: 0 (no injury) to 1-2+ (mild to moderate ATI) to 3+ (severe ATI). First group (N=7) consisted of renal biopsies that had no evidence of ATI or were obtained from patients with renal tumors and served as the control group. Group 2 (N=16) consisted of renal biopsies showing mild to moderate ATI. Group 3 (N=11) consisted of renal biopsies with severe ATI. All biopsy sections were stained for arginase-1 and CD68 via immunohistochemical techniques. Cytoplasmic granular staining of the two markers in proximal tubules was graded from 0 to 3+ in all groups. Staining scores and serum creatinine (sCr) levels were compared between 3 groups (ANOVA). Results: Serum creatinine levels were normal in controls (group 1, 0.72±0.10 mg/dL). In both groups with ATI, sCr levels were significantly higher in group 2 (2.27±0.33 mg/dL) and group 3 (7.27±1.13 mg/dL) (Table 1). Group 1 biopsies showed intact brush borders on PAS-stained sections (Figure 1A) and stained negatively for CD68 and arginase-1 (Figure 1B-1C). Group 2 cases showed mildly to moderately reduced brush borders on PAS-stained sections (Figure 1D) and stained positively for both CD68 and arginase-1, most at 2+ intensity in the cytoplasm of proximal tubules. Group 3 cases with severe ATI, however, showed positive CD68 staining but reduced or negative arginase-1 staining. Statistically, arginase-1 staining scores were significantly higher in group 2 (1.19±0.25) than group 1 (0.00±0.00, p=0.0085) and group 3 (0.46±0.15, p=0.0329). CD68 staining scores were not significantly different between group 2 (1.85±0.25) and group 3 (1.88±0.30), which were both significantly higher than group 1 (0.29±0.18, p=0.0001). Conclusions: Our data indicate that mild to moderate ATI is associated with high levels of arginase-1 staining in proximal tubular cells. This finding is compatible with phagocytotic capacity of proximal tubular cells to uptake circulating arginase-1. Reduced arginase-1 in severe ATI implies that severely injured proximal tubules lose their capacity to uptake arginase-1.
Anderson J, Blatt N, Afolayan-Oloye O, Kanaan H, Li W, Wickman L, et al. [Zhang P]. Injured proximal tubules stain positively for arginase-1 to indicate acute tubular injury (ATI). Lab Invest. 2023 Mar;103(3 Suppl.1):S1423-S1425. doi:10.1016/j.labinv.2023.100096