Inhibition of NLRP3 attenuates DOCA-Salt-Induced Hypertrophy and Endothelial Dysfunction in Male But Not Female Rats

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The immune system has been implicated in the development of hypertension and how the immune system is activated is of high interest. The NLRP3 inflammasome has been shown to contribute to the development of DOCA-salt hypertension in males, and we recently found that T cells contribute to sex differences in blood pressure with DOCA-salt. The goal of the current study was to test the hypothesis that males exhibit greater increases in NLRP3 with DOCA than females and that NLRP3 contributes to DOCA-salt-induced changes in end-organ hypertrophy. To determine the impact of DOCA on NLRP3, 11-week-old male and female Sprague Dawley (SD) rats were uninephrectomized (UNX) and randomized to control or 3 weeks of DOCA-salt treatment (n=6/group). NLRP3 and IL1β mRNA expression were measured via RT-PCR and data were compared via 2-way ANOVA. Renal NLRP3 and IL1β expression were greater in UNX control males than females. DOCA increased expression in both sexes, although the increases were greater in males (NLRP3: P interaction =0.03, P treatment <0.0001, P sex =0.0014; IL1β: P interaction =0.02, P treatment <0.0001, P sex =0.052). Additional UNX male and female SD rats were then randomized (n=6-10/group) to DOCA (200 mg) + saline or DOCA + saline + MCC950 (10 mg/kg/day). At 14 wks of age, rats were weighed and euthanized. The heart, spleen and remaining kidney were weighed and data were compared via 2-way ANOVA. The effectiveness of MCC950 was assessed by measuring renal NLPR3 mRNA expression at the end of the experiment. 3 weeks of MCC950 decreased NLRP3 in both sexes, although expression remained greater in males (P interaction =0.44, P treatment =0.0043, P sex =0.0001). 3 weeks of MCC950 attenuated increases in body weight in both sexes, although males of both groups weighed more than females. Due to differences in body weights, heart, spleen and kidney weights were normalized to body weight. Interestingly, heart:body weight ratio decreased in males and increased in females with MCC950 treatment. Neither splenic or kidney:body weight ratios were significantly altered by MCC950 treatment. These data support a role for the NLRP3 inflammasome to contribute to DOCA-salt induced increases in inflammation, and therefore increases in blood pressure, particularly in males. This work was supported by U54HL169191 (J.C.S and M.J.R), BX002604 (M.J.R) 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.

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