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Review
. 2021 Oct 28:12:754239.
doi: 10.3389/fphar.2021.754239. eCollection 2021.

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

Daiji Kawanami  1 , Yuichi Takashi  1 , Yoshimi Muta  1 , Naoki Oda  1 , Dai Nagata  1 , Hiroyuki Takahashi  1 , Makito Tanabe  1
Affiliations
Review

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

Daiji Kawanami et al. Front Pharmacol. .

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).

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Conflict of interest statement

DK receives research grants from Böehringer Ingelheim, Sumitomo Dainippon Pharma, and Bayer. DK receives lecture fee from Sanofi, Novo Nordisk Pharma, Ono Pharmaceutical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
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.
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References

    1. Agarwal R., Kolkhof P., Bakris G., Bauersachs J., Haller H., Wada T., et al. (2021). Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine. Eur. Heart J. 42, 152–161. 10.1093/eurheartj/ehaa736 - DOI - PMC - PubMed
    1. Al Dhaybi O., Bakris G. L. (2020). Non-steroidal Mineralocorticoid Antagonists: Prospects for Renoprotection in Diabetic Kidney Disease. Diabetes Obes. Metab. 22 (Suppl. 1), 69–76. 10.1111/dom.13983 - DOI - PubMed
    1. Amazit L., Le Billan F., Kolkhof P., Lamribet K., Viengchareun S., Fay M. R., et al. (2015). Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1. J. Biol. Chem. 290, 21876–21889. 10.1074/jbc.M115.657957 - DOI - PMC - PubMed
    1. Arai K., Morikawa Y., Ubukata N., Sugimoto K. (2020). Synergistic Reduction in Albuminuria in Type 2 Diabetic Mice by Esaxerenone (CS-3150), a Novel Nonsteroidal Selective Mineralocorticoid Receptor Blocker, Combined with an Angiotensin II Receptor Blocker. Hypertens. Res. 43, 1204–1213. 10.1038/s41440-020-0495-0 - DOI - PMC - PubMed
    1. Arriza J. L., Weinberger C., Cerelli G., Glaser T. M., Handelin B. L., Housman D. E., et al. (1987). Cloning of Human Mineralocorticoid Receptor Complementary DNA: Structural and Functional Kinship with the Glucocorticoid Receptor. Science 237, 268–275. 10.1126/science.3037703 - DOI - PubMed

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