Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension

Abstract

AimsRenal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension.Methods and resultsC57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25–40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na+], and albuminuria (each by 20–25%). None of the above parameters were altered by MCC950 in normotensive mice.ConclusionMCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…Taken together, these findings suggest efficacy of MCC950 in the acute stages following focal TBI in mice; however, it is unknown whether this compound exerts beneficial effects in other species and TBI models (e.g., diffuse TBI). While systemic MCC950 treatment has shown to be well-tolerated in hypertensive mice for as long as 28 days [98], pre-clinical TBI studies have yet to treat with MCC950 for longer than 7 days. Furthermore, the effects of early MCC950 intervention on chronic TBI recovery have not yet been investigated.…”

Research Progress on the Role of Inflammasomes in Kidney Disease

“…The expression of NLRP3 mRNA in renal biopsy specimens of patients with hypertensive or vascular nephrosclerosis is higher than that in normal kidneys, suggesting that NLRP3 plays a role in hypertension-related kidney disease [57]. Krishnan et al indicated that activation of the NLRP3 inflammasome in the kidney is associated with salt-sensitive hypertension [58,59]. Interestingly, in a hypertensive mouse model induced by angiotensin II, NLRP3 deficiency showed a protective effect on blood pressure, while the deletion of ASC did not [60].…”

“…Additionally, systemic deletion of NLRP3 in mice remarkably ameliorate proteinuria and podocyte damage [63]. In a hypertensive mouse model, MCC950, an NLRP3 inhibitor, can significantly reduce blood pressure and fibrosis, alleviate kidney inflammation, and protect against renal dysfunction [59]. Current studies have shown that the investigation of inflammasome-independent functions is of great significance to discover the pathogenesis of hypertension [64].…”

Inflammasome-independent role for NLRP3 in controlling innate anti-helminth immunity and tissue repair in the lung

“…One day prior to N. brasiliensis infection, mice were treated with either PBS vehicle or 10 mg/kg MCC950 (Sigma) by intraperitoneal injection in a 100 µl volume, a dose which has been previously shown to inhibit inflammasome activity (43). Injections were repeated daily up until the experimental endpoint.…”