NLRP3 Inhibition Attenuates Renal Injury to a Greater Degree in Male DOCA-Salt Rats Compared to Females

We have previously shown that sex differences in T cells contribute to greater increases in blood pressure (BP) in male rats following DOCA-salt treatment than in females. While T cells are known to contribute to the development of hypertension in both sexes, what drives T cell activation is still being investigated. The goal of the current study was to test the hypothesis that inhibition of NLRP3 after the initiation of DOCA-salt treatment will protect against increases in renal injury to a greater extent in male compared to female rats. 11-12 week-old male and female Sprague Dawley rats were uninephrectomized, implanted with a DOCA pellet (200 mg; subcutaneous) and given saline to drink. After 1 week, rats were randomized to receive saline as vehicle or the NLRP3 inhibitor, MCC950 (10 mg/kg) in saline drinking water for 2 more weeks (n=5/group). Plasma, urine and the remaining kidney were isolated to assess markers of inflammasome activation and renal injury in both sexes. Data were compared via 2-way ANOVA. Treatment with MCC950 attenuated renal NLRP3 and IL-18 protein levels (ELISA) in both sexes (NLRP3: P treatment <0.0001, P sex =0.05; IL-18: P treatment <0.0001, P sex =0.05), and the decrease was greater in males (P interaction =0.0007 for NLRP3 and P interaction =0.005 for IL-18). Urinary protein excretion and KIM-1, markers of renal and tubular injury, respectively tended to be greater in male compared to female DOCA-salt rats, and MCC950 treatment attenuated injury markers in both sexes (protein: P sex =0.87; P treatment =0.07; KIM-1: P sex =0.67; P treatment =0.06). However, MCC950 attenuated DOCA-induced increases in protein and KIM-1 excretions to a greater degree in males (P interaction =0.12 for protein and P interaction =0.21 for KIM-1). Our data suggest that NLRP3 contributes to the development of DOCA-salt induced renal injury in both sexes. Males were also found to have greater NLRP3-mediated increases in renal injury than females. These studies support further investigation of NLRP3 as a potential treatment option for hypertensive renal injury. 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.