Abstract
Excess mineralocorticoid receptor (MR) activation promotes target organ dysfunction, vascular injury and fibrosis. MR antagonists like eplerenone are used for treating heart failure, but their use is limited due to the compound class-inherent hyperkalemia risk. Here we present evidence that AZD9977, a first-in-class MR modulator shows cardio-renal protection despite a mechanism-based reduced liability to cause hyperkalemia. AZD9977 in vitro potency and binding mode to MR were characterized using reporter gene, binding, cofactor recruitment assays and X-ray crystallopgraphy. Organ protection was studied in uni-nephrectomised db/db mice and uni-nephrectomised rats administered aldosterone and high salt. Acute effects of single compound doses on urinary electrolyte excretion were tested in rats on a low salt diet. AZD9977 and eplerenone showed similar human MR in vitro potencies. Unlike eplerenone, AZD9977 is a partial MR antagonist due to its unique interaction pattern with MR, which results in a distinct recruitment of co-factor peptides when compared to eplerenone. AZD9977 dose dependently reduced albuminuria and improved kidney histopathology similar to eplerenone in db/db uni-nephrectomised mice and uni-nephrectomised rats. In acute testing, AZD9977 did not affect urinary Na+/K+ ratio, while eplerenone increased the Na+/K+ ratio dose dependently. AZD9977 is a selective MR modulator, retaining organ protection without acute effect on urinary electrolyte excretion. This predicts a reduced hyperkalemia risk and AZD9977 therefore has the potential to deliver a safe, efficacious treatment to patients prone to hyperkalemia.
Highlights
Mineralocorticoid receptor (MR, NR3C2) is a ligand activated transcription factor belonging to the oxysteroid nuclear hormone receptor class
Pathological activation of mineralocorticoid receptor (MR) leads to an increased risk for cardiovascular (CV) events [7, 8] and MR blockade using the marketed MR antagonists (MRA) spironolactone and eplerenone has proven to be an effective therapy for treatment of heart failure and hypertension [9,10,11]
High levels of circulating aldosterone are associated with endothelial dysfunction [13,14,15,16] and can lead to the development of impaired renal function characterized by kidney fibrosis, hyperfiltration and proteinuria [12, 17]
Summary
Mineralocorticoid receptor (MR, NR3C2) is a ligand activated transcription factor belonging to the oxysteroid nuclear hormone receptor class. MR is expressed in a wide variety of different non-epithelial cell types and tissues [2,3,4,5], where it mediates a large diversity of cell type specific effects. MR activation in non-epithelial tissues promotes target organ dysfunction by stimulating inflammation, oxidative stress and fibrosis [6]. A growing body of pre-clinical and clinical evidence supports a role of MR activation as an independent and powerful mediator of renal vascular disease and chronic kidney disease (CKD) [12]. High levels of circulating aldosterone are associated with endothelial dysfunction [13,14,15,16] and can lead to the development of impaired renal function characterized by kidney fibrosis, hyperfiltration and proteinuria [12, 17]
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