Esaxerenone Attenuates Aldosterone-Induced Mitochondrial Damage-Mediated Pyroptosis in Mouse Aorta and Rat Vascular Smooth Muscle Cells.

BACKGROUND: Vascular smooth muscle cell (VSMC) injury caused by the inflammatory response plays a key role in cardiovascular disease (CVD), and the vasoprotective effects of mineralocorticoid receptor blockers (MRBs) support the role of mineralocorticoid receptor (MR) activation. METHODS: C57BL/6 mice and VSMCs isolated from rats were treated with aldosterone and esaxerenone. Caspase-1, GSDMD-N, IL-1ß, and NR3C2 expression and DNA damage in aortic VSMCs were detected using immunohistochemistry, Western blotting, and TUNEL staining. Mitochondrial changes were detected by transmission electron microscopy (TEM). Reactive oxygen species (ROS), MitoTracker, JC-I, mitochondrial respiratory chain complexes I-V, and NR3C2 were detected using immunofluorescence and flow cytometry. Pyroptosis was detected with scanning electron microscopy (SEM). RESULTS: After aldosterone treatment, the number of TUNEL-positive cells increased significantly, and the expression of caspase-1, GSDMD-N, and IL-1ß increased. TEM revealed mitochondrial damage, and SEM revealed specific pyroptotic changes, such as cell membrane pore changes and cytoplasmic extravasation. Increased ROS levels and nuclear translocation of NR3C2 were also observed. These pyroptosis-related changes were reversed by esaxerenone. CONCLUSIONS: Aldosterone activates the MR and mediates mitochondrial damage, thereby inducing pyroptosis in VSMCs via the NLRP3/caspase-1 pathway. Esaxerenone inhibits MR activation and reduces mitochondrial damage and oxidative stress, thereby inhibiting pyroptosis.

Eplerenone inhibits the macrophage-to-myofibroblast transition in rats with UUO-induced type 4 cardiorenal syndrome through the MR/CTGF pathway.

Cardiovascular complications are the leading causes of death in patients with chronic kidney disease (CKD), accounting for approximately 50% of deaths. Despite significant advances in the understanding of cardiac disease due to CKD, the underlying mechanisms involved in many pathological changes have not been fully elucidated. In our previous study, we observed severe fibrosis in the contralateral kidney of a 6-month-old rat UUO model. In the present experiment, we also observed severe fibrosis in the hearts of rats subjected to UUO and the macrophage-to-myofibroblast transition (MMT). These effects were inhibited by the mineralocorticoid receptor (MR) blocker eplerenone. Notably, in vitro, aldosterone-activated MR induced the MMT and subsequently promoted the secretion of CTGF, the target of MR, from macrophages; these changes were inhibited by eplerenone. The CTGF also induced the MMT and both the aldosterone and CTGF-induced MMT could be alleviated by the CTGF blocker. In conclusion, our results suggest that targeting the MR/CTGF pathway to inhibit the MMT may be an effective therapeutic strategy for the treatment of cardiac fibrosis.

Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-ß1 pathway in mice induced with aldosterone.

Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-ß1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-ß1 pathway may be an effective therapeutic strategy for renal fibrosis.

Eplerenone inhibits UUO-induced lymphangiogenesis and cardiac fibrosis by attenuating inflammatory injury.

Cardiorenal syndrome (CRS) is the leading cause of death associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, the underlying mechanisms of CRS are still poorly understood. Here, we studied a CKD model of unilateral ureteral obstruction (UUO) and observed pathological cardiac fibrosis and lymphangiogenesis in 180-day old UUO rats, in which inflammatory injury plays a major role. In addition, treatment of UUO rats with eplerenone, a mineralocorticoid receptor blocker (MRB), significantly reduced cardiac lymphangiogenesis and fibrosis. In conclusion, our experimental results showed that cardiac lymphangiogenesis in long-term UUO rats may be involved in the formation of cardiac fibrosis and that eplerenone can alleviate lymphangiogenesis and cardiac fibrosis by inhibiting inflammation.