Abstract TAC236: NLPR3 inflammasome inhibitor attenuates autoimmune mediated hypertension in female mice

Immune mechanisms directly contribute to the pathogenesis of hypertension, and autoimmune diseases like systemic lupus erythematosus (SLE) are characterized by prevalent hypertension, cardiovascular and renal risk. The pathways involved in autoimmune mediated hypertension remain unclear. In humans and animal models, mitochondrial dysfunction is implicated in SLE disease progression. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is activated in SLE and can exacerbate mitochondrial dysfunction. Renal mitochondrial respiration via complex I progressively decreases (in pmol O2/mg protein/complex IV, 0.38±0.04 and 0.28±0.02 at 28 and 30 weeks of age respectively, p=0.02) in an established hypertensive model of SLE (female NZBWF1 mice). We hypothesized that the NLRP3 inflammasome promotes mitochondrial dysfunction and the development of hypertension in the female NZBWF1 model of SLE. To test this hypothesis, 22-week-old female NZBWF1 (SLE, n= 22) were treated with the NLRP3 inhibitor, MCC950 (40 mg/kg/wk, i.p.) or vehicle (sterile saline, n= 25) for 6 weeks. Mean arterial pressure (MAP in mmHg) was recorded in a subset of conscious freely moving mice via carotid artery catheters. MAP was lower in MCC950 treated SLE mice compared to vehicle treated mice at the end of the study (136±3, n=15 vs 145±3, n=9, p=0.04). Anti-dsDNA autoantibodies levels were measured via ELISA before and after the 6-week treatment period. SLE mice treated with MCC950 had lower circulating anti-dsDNA autoantibodies compared to vehicle treated mice at the end of the study (in kU/mL, 60±24 vs 149±54.9, n=8/group, p=0.03). Renal mitochondrial respiration via complex I was not changed in MCC950 treated SLE mice (in pmol O2/mg protein/complex IV, 0.37±0.03, n= 10 vs 0.38±0.04, n= 9, p=0.83). Neither urinary albumin excretion (in µg/24hrs, 165±68 vs 112±66, n=12/group, p=0.59) nor glomerular injury score in hematoxylin and eosin stained sections (1.95±0.12 vs 1.71±0.15, n=8/group, p=0.22) were changed in MCC950 treated SLE mice. These novel findings suggest that NLRP3 inflammasome inhibitors can serve as potential therapeutics to attenuate the pathogenesis of hypertension in SLE, perhaps through mitigating the production of autoantibodies, and independent of mitochondrial function or renal injury.