Editorial
Nonsteroidal Mineralocorticoid Receptor Antagonists and Protection Against Cardiovascular Disease in Patients with Diabetes Mellitus
2023 年 30 巻 4 号 p. 321-322
詳細
2023 年 30 巻 4 号 p. 321-322
See article vol. 30: 326-334
Increased activation of the systemic and local renin-angiotensin-aldosterone system (RAAS) is often observed in people with obesity and insulin resistance, and this activation plays an important role in the development of type 2 diabetes mellitus (T2DM) and in cardio-renal complications1). Aldosterone is a steroid hormone that regulates blood pressure and cardiovascular (CV) homeostasis by acting on renal and vascular mineralocorticoid receptors (MRs) mainly via the reabsorption of sodium and excretion of potassium in the distal tubules and by collecting ducts of the nephron2, 3). MRs are expressed in endothelial cells, vascular smooth muscle cells, adipocytes, immune cells, skeletal muscle cells, and cardiomyocytes4). When dysregulated such as in people with obesity or diabetes mellitus, aldosterone is hazardous and contributes to the development and progression of CV and kidney disease1).
MR antagonists (MRAs) comprise steroidal MRAs such as spironolactone and eplerenone and nonsteroidal MRAs such as esaxerenone and finerenone5, 6). Nonsteroidal MRAs have demonstrated crucial differences in their distribution, binding mode to MRs, and subsequent gene expression compared with steroidal MRAs5, 6). Because nonsteroidal MRAs are preferentially concentrated in the kidneys and CV system, they appear to demonstrate a better benefit–risk ratio than steroidal MRAs. Benefits include antimetabolic and antihemodynamic actions, whereas risks include acute renal dysfunction, sexual side effects, and hyperkakemia5, 6).
Addition of the nonsteroidal MRA finerenone to optimal RAAS blockade reduced CV and kidney outcomes in two large phase Ⅲ trials in patients with chronic kidney disease (CKD) and T2D7, 8). The FIDELIO-DKD and FIGARO-DKD studies comprise the largest CKD outcomes program to date and determined the effect of nonsteroidal MR antagonism by finerenone on CKD progression and CV mortality and morbidity in patients with CKD and T2D7, 8). Currently, the underlying mechanisms of the benefits of MRAs have not yet been clarified.
Vascular endothelium functions as a mechanical barrier and an autocrine and paracrine organ and contains complex sensory and signal transduction networks that regulate various CV functions9). A healthy resilient endothelium is essential not only for the normal development but also for the optimal functioning of the entire CV system throughout a lifetime. Endothelial dysfunction contributes directly to the pathogenesis of a wide range of CV diseases, including T2DM.
In the current issue, Munkhjargal et al.10) found that esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. They indicated that esaxerenone has potential vascular protective effects in mice with diabetes. As shown in Fig.1, protection of diabetes-associated cardio-renal events may be hypothesized to be via MRA in RAAS-dependent and -independent pathways. Further studies are needed to clarify these underlying mechanisms.
ROS: reactive oxygen species; eNOS: endothelium-derived nitric oxide synthase; RAAS: renin-angiotensin-aldosterone system.
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