高血圧ジャーナル: オープンアクセス

Renin-Dependent Hypertension in Mice Requires the NLRP3- Inflammasome

Abstract

Qing Wang, Alexander So, Jürg Nussberger, Annette Ives, Nathaliane Bagnoud, Stephan Shäefer, Jürg Tschopp and Michel Burnier

Objective: Recent studies have implicated an enhanced secretion of IL1β through activation of the Nod-like receptor family, pyrin domain containing 3 (Nlrp3)-inflammasome as the pro-inflammatory signal in animal models of the gout, chronic kidney disease (CKD), atherosclerosis, metabolic syndrome, type 2 diabetes mellitus, but its contribution to hypertension is not established. We aimed to demonstrate the role of the Nlrp3-inflammasome in the two-kidneys, one clip (2K1C) Goldblatt model of hypertension in Nlrp3-/- and apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc)-/- and wild type control male mice.

Study design: 2K1C hypertension was generated by narrowing left renal artery using U-shaped stainless steel clip. BP and heart rate were recorded intra-arterially with a computerized data-acquisition system in conscious mice. Plasma renin activity and concentration were measured by radioimmunoassay. Renal transcript levels of Nlrp3, Asc, Casp1, IL1A, IL1β, and IL6 were assessed by RT-Q-PCR.

Results: Results show that Nlrp3-/- and Asc-/- mice are protected from developing hypertension and have lower circulating levels of plasma renin and serum amyloid A (SAA) and IL6, in comparison to wild type (WT) control mice. RNA levels of SAA, Nlrp3, and IL1β are increased in the ischemic kidney of the WT control mice. Administration of anti-IL1β antibody to the WT control mice attenuated the increase of blood pressure and renin in the 2K1C model. The results suggest that NALP3 inflammasome has an impact on blood pressure and renin secretion during renal hypoperfusion induced by renal arterial clip and contributes to renin-dependent renovascular hypertension.

Conclusion: These findings show that Nlrp3-inflammasome mediated production of IL1 is linked to the development of renovascular hypertension and might be a novel target for the treatment of renovascular hypertension, CKD and other inflammatory diseases with hypertension.