Endocrinol Metab.  2023 Feb;38(1):43-55. 10.3803/EnM.2022.1629.

Renal Protection of Mineralocorticoid Receptor Antagonist, Finerenone, in Diabetic Kidney Disease

• Kim DL
• Lee SE
• Kim NH

• KMID: 2539816
• DOI: http://doi.org/10.3803/EnM.2022.1629

Abstract

Chronic kidney disease (CKD) is the most common cause of end-stage renal disease in patients with type 2 diabetes mellitus (T2DM). CKD increases the risk of cardiovascular diseases; therefore, its prevention and treatment are important. The prevention of diabetic kidney disease (DKD) can be achieved through intensive glycemic control and blood pressure management. Additionally, DKD treatment aims to reduce albuminuria and improve kidney function. In patients with T2DM, renin-angiotensin-aldosterone system inhibitors, sodium glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can delay the progression of DKD. Hence, there is a need for novel treatments that can effectively suppress DKD progression. Finerenone is a first-in-class nonsteroidal mineralocorticoid receptor antagonist with clinically proven efficacy in improving albuminuria, estimated glomerular filtration rate, and risk of cardiovascular events in early and advanced DKD. Therefore, finerenone is a promising treatment option to delay DKD progression. This article reviews the mechanism of renal effects and major clinical outcomes of finerenone in DKD.

Keyword

Renal insufficiency, chronic; Diabetic nephropathies; Finerenone; Mineralocorticoid receptor antagonists; Diabetes mellitus, type 2

Figure

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  Figure 1. Mechanism of steroidal mineralocorticoid receptor antagonists (MRAs) and nonsteroidal MRA finerenone. Aldosterone binds to mineralocorticoid receptors (MRs) and promotes a conformational change after which it is translocated into the nucleus. The MR then binds to specific hormone response elements, recruits transcriptional cofactors, and then initiates the transcription of target genes. MR overactivation promotes the expression of proinflammatory and profibrotic genes and the activation of signaling pathways implicated in the progression of renal disease. Both steroidal and nonsteroidal MRAs bind to MRs, which causes a different conformational change that inhibits aldosterone from binding to MRs. This prevents the downstream transcription of proinflammatory and profibrotic factors. Steroidal MRAs can interact with cofactors that affect gene transcription; hence, they function as partial MR agonists. Finerenone inhibits cofactor recruitment to the MR from the cytoplasm to the nucleus. Inhibition of MR cofactor binding can occur even in the absence of aldosterone. Additionally, the gene regulation profile by finerenone differs from that for steroidal MRAs. The anti-inflammatory and antifibrotic activities of finerenone are more potent than those of steroidal MRAs. HRE, hormone response element; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cell; AP-1, activator protein-1.

• 

  Figure 2. Renoprotective effects of finerenone in diabetic kidney. In diabetic kidney, mineralocorticoid receptor (MR) activation induces deleterious glomerular alternation and tubulointerstitial fibrosis. Finerenone binds to MRs and prevents the transcription of proinflammatory and profibrotic factors in renal cells including podocytes, mesangial cells, macrophage, endothelial cells, and fibroblasts. GBM, glomerular basement membrane; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; CCL-2, C-C motifchemokine ligand 2; MCP-1, monocyte chemoattractant protein-1; TGF-β, transforming growth factor β; PAI-1, plasminogen activator inhibitor-1; CTGF, connective tissue growth factor.

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