Aldosterone activates NLRP3/inflammasome in the vasculature of type 2 diabetic mice.
Authors: dos Santos Ferreira Nathanne , Bruder‐Nascimento Thiago , Pereira Camila André , Zanotto Camila Zillioto , da Silva Josiane Fernandes , de Cássia Tostes Rita 
Published: June 2021

Introduction

Aldosterone levels were increased in diabetic patients and animals with type 2 diabetes mellitus (DM2). The excess of aldosterone (aldo) aggravates endothelial dysfunction in diabetes by promoting insulin resistance, fibrosis, oxidative stress and inflammation. The pro‐inflammatory cytokines IL‐1β was release by activation of NOD‐like receptors that comprise a group of pattern recognition receptors involved in a variety of host innate immune responses. Recently, our group demonstrated the involvement of NLRP3 in aldosterone‐induced vascular dysfunction. So, considering that we hypothesized which aldosterone activates the inflammasome platform in the vasculature of DM2 mice.

Methods

Mesenteric arteries from control (db/+) and diabetic (db/db) mice treated with vehicle or spironolactone (spiro – mineralocorticoid receptor (MR) antagonist, 50 mg/Kg/day) or NLRP3 antagonist (MCC950, 10 mg/Kg/day) were used to determine vascular reactivity and aldosterone‐induced inflammasome activation. The plasma of animals was used to evaluated IL‐1β and aldosterone levels.

Results

Db/db mice exhibited increased IL‐1β levels, increased vascular expression/activation of caspase‐1, as well reduced acetylcholine (ACh) vasodilation, compared to control (Cont) mice. Spironolactone and MCC950 treatment decreased plasma IL‐1β levels [(pg/mL) (Cont: 44.4±9.9 n=7; Cont+Spiro: 27.2±8.3 n=5, db/db: 85.4±21.9 n=7; db/db+Spiro: 11.6±3.2 n=6, p<0.05) and ( Cont: 2.0±2.0 n=6; Cont+MCC950: 0.0±0.0 n=3, db/db: 318.2±97.6 n=5; db/db+MCC950: 37.5±28.8 n=5, p<0.05)]. Spiro treatment but not MCC950 reduced caspase‐1 activity/expression in mesenteric arteries from db/db mice (arbitrary units (a.u.) Cont: 1.0±0.1 n=6; Cont+Spiro: 0.8±0.2 n=5, db/db: 2.4±0.6 n=4; db/db+Spiro: 0.5±0.2 n=6, p<0.05) and ( Cont: 1.0±0.4 n=4; Cont+MCC950: 0.8±0.2 n=4, db/db: 2.0±0.9 n=4; db/db+MCC950: 1.1±0.2 n=5, p>0.05)]. Spiro treatment reduced glucose levels in db/db mice [Glucose (mg/dL), Cont: 156.1±5.7 n=10; Cont+spiro: 150.2±7.3 n=9; db/db: 265.1±17.4 n=12; db/db+spiro: 185.5±21.6 n=8, p<0.05] and improved Ach vasodilation in diabetic mice [Emax (% of relaxation) Cont: 78.5±4.1 n=7; control+spiro: 77.04±3.83 n=3; db/db: 40.5±6.4 n=8; db/db+spiro: 62.83±5.89 n=6, p<0.05]. Despite treatment with MCC950 does not reduce the aldosterone plasma levels [Aldo (pg/mL), Cont: 222.0±29.3 n=6; Cont+MC9950:183.7±81.0 n=3, db/db:552.7±85.4 n=5; db/db+MCC950:434.2±73.8 n=5, p>0.05] and glucose levels in db/db mice [Glucose (mg/dL), Cont: 178.3±9.1 n=6; Cont+MCC950: 166.3±4.8 n=3, db/db: 402.0±36.1 n=4; db/db+MCC950: 317.8±36.5 n=5, p>0.05], MCC950 improve the maximum response (Emax) of ACh [(Emax (% of relaxation) Cont: 78.5±4.1 n=6; Cont+MCC950: 77.0±3.8 n=3; db/db: 40.5±6.4 n=5; db/db+MCC950: 62.8±5.9 n=5, p<0.05].

Conclusion

These results suggest that aldosterone activates the inflammasome platform in the vasculature of DM2 mice. The MR and NLRP3 receptors activation plays a crucial role on aldosterone‐induced in diabetes‐associated vascular dysfunction and inflammation.

Support or Funding Information

CAPES, CNPq, FAPESP

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.