Premenopausal female protection from angiotensin II-induced hypertension is eliminated with the loss of calprotectin

Premenopausal females are protected from angiotensin II (ANG II) induced hypertension in comparison to males. However, in post-menopausal females, protection is lost and ANG II induces hypertension and an associated pro-inflammatory response in the kidney, suggesting estrogen’s protective role in modulating immune responses. RNAseq studies identified higher expression of calprotectin in female immune cells following ANGII infusion. Calprotectin, a highly expressed protein in neutrophils, is upregulated by acute renal injury. Therefore, we examined how a loss of calprotectin would impact hypertension induced renal damage in a sex specific manner. In a global calprotectin knockout, we infused ANG II to examine blood pressure responses and determined that females lost their protection against hypertension; here we hypothesized that loss of protection was due to changes in GFR and sodium handling. 12-week-old male and female Calprotectin KO (S100a9-/-) mice were infused with ANG II (800 ng/kg/min) via osmotic minipump for 14 days. Systolic blood pressure (SBP) was measured via tail cuff. Glomerular filtration rate was measured transdermally (medibeacon). To evaluate natriuretic capacity and NKCC2 activity, saline and furosemide challenges were performed at day 12 of ANG II infusion and compared to wildtype responses. Both male and female S100a9-/- mice had a significant increase in blood pressure after 13 days of ANG II infusion (SBP male ANG II: Δ53 ± 6.4 mmHg *p< 0.05 vs. to controls, SBP female ANG II Δ31.3 ± 9.7 mmHg *p< 0.05 vs. controls). However, only female mice infused with ANG II showed a significant decrease in GFR (female control 302± 35 µL/min vs. female ANG II 177 ± 16 µL/min, *p< 0.05, male control 287 ± 23 µL/min vs. male ANG II 310 ± 23 µL/min, p >0.05). Both males and females infused with ANG II had a significant reduction in diuresis following a saline challenge (male control 8.8 ± 0.5 µEq/4hr/g B.W vs. male ANG II 5.8 ± 0.7 µEq/4hr/g B.W, *p< 0.05, female control 6.6 ± 0.4 µEq/4hr/g B.W vs. female ANG II 4.6 ± 0.6 µEq/4hr/g B.W, *p< 0.05). However, when challenging with furosemide injection only females infused with ANG II had a significant increase in urine output, indicating increased NKCC2 activity (female control 3.4 ± 0.3 µEq/2hr/g B.W vs. female ANG II 6.01 ± 1.1 µEq/2hr/g B.W *p< 0.05, male control 4.7 ± 0.3 µEq/2hr/g B.W vs male ANG II 4.9 ± 0.9 µEq/2hr/g B.W, p >0.05). The results show that calprotectin is necessary for preserved natriuresis of ANG II infused females. The loss of protection in calprotectin KO female mice implicates higher activity of NKCC2, suggesting a new calprotectin dependent modulation of tubular function. 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.