Premenopausal females are protected from angiotensin II (ANG II) induced hypertension in comparison to males. However, in post-menopausal females, protection is lost against ANG II induced hypertension and the renal pro-inflammatory response, suggesting estrogen’s protective role via the modulation of immune cells. RNAseq studies identified a sex difference in immune cell calprotectin (s100a8/a9), an inflammatory protein complex highly abundant in neutrophils and linked to renal injury. Therefore, we examined how a loss in calprotectin would disrupt kidney immune profiles in a sex-dependent manner during hypertension. At baseline, WT males had a significant increase in neutrophils (Ly6G+) that were all S100a9+ (male 3. 6×10⁴ vs female 4. 2×10³ cells, *p=0. 02). We also identified a significant increase in cd11b+ cells in male kidneys (male 1. 2×10⁵ cells vs female 6. 1×10⁴, *p=0. 02). Compared to females, S100a9+cd11b+ cells were significantly higher in male kidneys (male 3. 8×10⁴ cells vs female 4. 3 ×10³, *p=0. 02). Interestingly, S100a9+ Tregs and S100a9+ non-Tregs were almost undetectable in male and female kidneys but present in the spleen. In a global calprotectin knockout (S100a9-/-), we infused ANG II to examine blood pressure responses and determined that females lost their protection against hypertension. To determine if sex differences in renal gene expression were modified by loss of S100a9-/- we performed bulk RNA sequencing of kidneys from male and female WT and S100a9-/- mice (n=3 per group). Significant sex differences were identified in the expression of ion transporters and immune pathways between WT and S100a9-/- mice. SLC22A7 (OAT2) was significantly decreased and SLC25A25 (mitochondrial transport protein) was significantly increased (3 fold) in female S100a9-/- kidneys vs WT. The expression of innate immune response modulator Wdfy1 was significantly increased in both male and female S100a9-/- kidneys compared to WT (3-fold in both sexes), in contrast, Fgb (fibrinogen B beta) expression was significantly decreased in male S100a9-/- kidneys. Flow cytometry analysis revealed that S100a9-/- ANG II females, but not males, had significantly increased neutrophils infiltration into the kidney compared to controls (ANG II females, 1. 3 ×10⁴ vs control females 7. 3×10³ cells, *p=0. 001), indicating that S100a9-/- neutrophils may modulate kidney function in S100a9-/- females during hypertension. Surprisingly, renal dendritic cells (cd11c+) were significantly reduced in ANG II-infused S100a9-/- females, but not in males, (ANG II females 3. 4×10⁴ vs control females 6. 9×10⁴ cells, *p=0. 02). In contrast, renal macrophages (cd11b+) remained unchanged across all groups in S100a9-/- with and without ANG II. The results show that calprotectin is a critical sex-dependent regulator of renal myeloid populations and the presence of calprotectin in females may protect from renal inflammation during ANG II-induced hypertension. This project is funded by U2C DK133422 & TL1 DK139566 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Shelke et al. (2026) studied this question.