Abstract 005: A Small-molecule Inhibitor of NLRP3 Inflammasome Activity, MCC950, Reduces Blood Pressure and Restores Renal Function in Hypertensive Mice

Abstract

Inflammasomes are a family of interleukin-1 processing complexes and master regulators of inflammation. We recently showed that both one-kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)- and angiotensin II-dependent hypertension in mice are associated with elevated expression of the NLRP3 inflammasome in the kidneys. Moreover, genetic deficiency of a key subunit critical for NLRP3 inflammasome activity protected mice against renal inflammation and chronic pressor responses associated with these models. As a step towards translation of these findings into new therapies, here we investigated whether a highly specific small-molecule inhibitor of NLRP3 inflammasome activity, MCC950, similarly reduces the deleterious effects of 1K/DOCA/salt on blood pressure (BP) and renal function. Male C57BL6/J mice were implanted with telemetry probes for continuous recording of BP (mean arterial (MAP), systolic, diastolic) and heart rate (HR), or placed in metabolic cages for 24 h urine collections to assess renal function. Once baseline parameters were established, mice were uninephrectomized, received a DOCA pellet (2.4 mg/kg/d, s.c. ) and were given 0.9% saline to drink. Following establishment of hypertension (10 d), mice were implanted with osmotic pumps containing either MCC950 (10 mg/kg/d, s.c. ) or vehicle (saline) and followed for 28 d. MAP increased from 102 ± 2 to 133 ± 3 mmHg over the 10 d following 1K/DOCA/salt surgery. In vehicle-treated mice, MAP remained at this elevated level until the end of the treatment period. By contrast, MAP of mice treated with MCC950 gradually declined such that at day 38 it was 15 mmHg lower than that of vehicle-treated mice. Systolic and diastolic BP response was similar to MAP, whereas HR was unaffected by MCC950. Urine, Na + and albumin excretion, and osmolality were all markedly increased after 10 d of 1K/DOCA/salt treatment. Consistent with its effect on BP, MCC950 decreased each of these parameters by 30-40%, whereas vehicle had no effects. In conclusion, we have shown that an inhibitor of NLRP3 inflammasome activation reduces BP and restores renal function in mice with established hypertension, highlighting MCC950 as a promising candidate for future therapies.