NLPR3 inflammasome inhibitor attenuates hypertension in female mice with SLE

Background: Systemic lupus erythematous (SLE) is an autoimmune disorder that primarily affects women of childbearing age. Cardiovascular disease is the major cause of mortality in women with SLE and hypertension is markedly increased in these patients. Published data from the Ryan laboratory demonstrated a central role for circulating autoantibodies in the development of autoimmune mediated hypertension. The pathways involved in autoantibody-mediated hypertension remain unclear. In humans and animal models, mitochondrial dysfunction is implicated in SLE disease progression. Mitochondrial dysfunction activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome during SLE, leading to the production of inflammatory cytokines (IL-1b and IL-18) and caspase-1, that can further exacerbate mitochondrial dysfunction. However, whether renal mitochondrial dysfunction and NLRP3 inflammasome activation promote SLE-associated hypertension has not been studied. Hypothesis: Renal mitochondrial dysfunction and the NLRP3 inflammasome promote the development of hypertension in an established female mouse model of SLE. Methods and Results: An antigen array was performed (University of Texas Southwestern Genomics & Microarray Core Facility) using plasma from female SLE (30-week-old female NZBWF1, n=8) and healthy control (30-week-old female NZWLacJ, n=7) mice. The array showed that SLE mice produced antibodies to mitochondrial antigens cardiolipin, cytochrome c, and pyruvate dehydrogenase (p<0.02 vs control mice). Renal mitochondrial function was tested using high resolution respirometry (Oroboros Instruments) in whole kidney homogenates from 30-week-old female SLE (n=12) and controls (n=12). Complex I (CI) and Complex II (CII) coupled respiration, an estimation of oxidative phosphorylation, and uncoupled respiration, an estimation of maximal electron transport (ETS), were impaired in SLE mice (in pmol O 2 /mg protein, CI: 88±4 vs 70±5, CI+CII: 212±11 vs 172±13.2, ETS: 225±13 vs 182±14 p<0.03). To investigate the link between mitochondria, NLRP3 inflammasome, and autoimmune mediated hypertension, female SLE mice (22-week-old NZBWF1) and female controls (22-week-old NZWLacJ) were treated with the NLRP3 inhibitor, MCC950 (40 mg/kg/wk, i.p.) or vehicle (sterile saline) for 6 weeks. Mean arterial pressure (MAP in mmHg) was recorded from conscious freely moving mice via carotid artery catheters. MAP was increased in SLE mice compared to controls (149±4 vs 113±7, n=4-6, p<0.001). MAP was lower in SLE mice treated with MCC950 (133±4, n=9, p<0.05) compared to vehicle treated SLE mice. Unexpectedly, control mice treated with MCC950 (133±2, n=8, p<0.01) had higher blood pressure than vehicle treated control mice. Conclusion: These data support the potential mechanistic contribution of mitochondrial dysfunction and the NLRP3 inflammasome in the development of autoimmune mediated hypertension in SLE. This work was supported by U54HL169191 & BX002604 to MJR. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract. 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.