Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide. Mineralocorticoid receptor (MR) plays an important role in the development of DKD. A series of preclinical studies revealed that MR is overactivated under diabetic conditions, resulting in promoting inflammatory and fibrotic process in the kidney. Clinical studies demonstrated the usefulness of MR antagonists (MRAs), such as spironolactone and eplerenone, on DKD. However, concerns regarding their selectivity for MR and hyperkalemia have remained for these steroidal MRAs. Recently, nonsteroidal MRAs, including finerenone, have been developed. These agents are highly selective and have potent anti-inflammatory and anti-fibrotic properties with a low risk of hyperkalemia. We herein review the current knowledge and future perspectives of MRAs in DKD treatment.

Keywords: aldosterone; diabetic kidney disease; diabetic nephropathy; mineralocorticoid receptor (MR); mineralocorticoid receptor antagonist (MRA).

FIGURE 1

Regulation of MR in DKD. Upon the binding of aldosterone to MR, the bound MR translocates into the nucleus and binds to the HRE of the target gene to initiate transcription. CYP11B2 is expressed in the kidney, and local aldosterone production occurs in DKD, leading to MR overactivation. MR overactivation stimulates SGK1 and induces subsequent inflammation/oxidative stress, apoptosis, and fibrotic process. Furthermore, ligand-independent MR activation by Rac1 has been reported. MR: mineralocorticoid receptor, DKD: diabetic kidney disease, HRE: Hormone responsive element, SGK1: Serum and glucocorticoid-regulated kinase 1, TGF-β: transforming growth factor beta, NF-κB: Nuclear factor κB, ROS: reactive oxygen species, Rac1: The small guanosine triphosphatase (GTPase) RAS-related C3 botulinus toxin substrate 1.