Inhibition of NLRP3 attenuated DOCA-salt-induced increases in blood pressure, inflammation, and renal injury in male and female rats

We and others have previously shown that DOCA-salt induces greater increases in blood pressure (BP) in males than in females, and we previously reported that T cells contribute to sex differences in DOCA-salt hypertension. NLRP3 has been implicated in DOCA-salt hypertension in male mice, but little is known regarding the role of NLRP3 in females. The goal of the current study was to determine the impact of NLRP3 inhibition on BP, renal inflammation and renal injury in male and female DOCA-salt hypertensive rats. We hypothesize that inhibition of NLRP3 will attenuate DOCA-salt-induced increases in BP, renal inflammation and renal injury in male and female DOCA-salt rats, although we expect the effect to be greater in males. 11–12-wk-old male and female Sprague Dawley rats were uninephrectomized and randomized into 2 groups (n=6-7/group): 1) controls received DOCA and saline and 2) treated rats received DOCA plus the NLRP3 inhibitor MCC950 (10 mg/kg/day in saline) from 11-14 wks of age. At 14-wks-of-age rats were euthanized, terminal plasma samples were collected, and the remaining kidney was isolated and processed for biochemical analysis, histology, and T cell analysis using flow cytometry. Data were compared via two-way ANOVA. DOCA treatment increased BP in males (105±4 to 190±1 mmHg) and females (97±3 to 167±5 mmHg), and treatment with MCC950 attenuated DOCA-induced increases in BP in both sexes (males: 107±3 vs. 174±2 mmHg; females: 98±3 vs. 159±7 mmHg; P sex <0.0001, P treatment <0.0001, P interaction =0.02). The effectiveness of MCC950 was confirmed by measuring renal NLRP3 and IL-1β protein levels via ELISA. MCC950 significantly decreased NLRP3 and IL-1β in both sexes (NLRP3: P treatment <0.001, P sex =0.77, P interaction =0.99; IL-1β: P treatment <0.004, P sex =0.003, P interaction =0.97). MCC950 also significantly attenuated DOCA-induced increases in renal CD4 + T cells and Th17 cells to a greater degree in males than in females (CD4+: P treatment <0.001, P sex =0.03, P interaction =0.04; Th17 cells: P treatment <0.001, P sex =0.001, P interaction =0.04). MCC950 improved creatinine clearance, an indicator of renal function, in males without significant changes in female DOCA-salt rats (P treatment =0.09, P sex =0.001, P interaction =0.02). Utilizing PASH staining, histological examination indicated that MCC950 treatment also decreased glomerulosclerosis in both sexes (P treatment =0.002, P sex =0.35, P interaction =0.22). Our data suggests that NLRP3 contributes to the development of DOCA-salt induced elevations in BP, renal inflammation and injury in both sexes, although the effects were more pronounced in males. Study supported by NIHU54HL169191 and 5R01DK134695 to JCS This abstract was presented at the American Physiology Summit 2025 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.