A Novel Aldosterone Antagonist Limits Renal Injury in 5/6 Nephrectomy

Abstract

Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD.

Vascular and inflammatory mineralocorticoid receptors in kidney disease

“…65 The protection conferred by endothelial MR deficiency was due to increased eNOS activation and reduced oxidative stress, highlighting the important role of endothelial MRs for eNOS activation. 70 The protection conferred by MR antagonism in this model is not limited to the kidney, as finerenone was also able to improve the diastolic dysfunction in mice with CKD induced by subtotal nephrectomy. Indeed, specific EnNaC deletion in the endothelium showed a similar beneficial effect as endothelial MR deletion in western diet-induced obesity on aortic stiffness and fibrosis, but the impact on the kidney was not assessed.…”

“…69 The non-steroidal aldosterone antagonist Ly has a similar protective effect in 5/6 nephrectomy, as shown by reduced albuminuria and kidney hypertrophy. 70 The protection conferred by MR antagonism in this model is not limited to the kidney, as finerenone was also able to improve the diastolic dysfunction in mice with CKD induced by subtotal nephrectomy. 71 Mineralocorticoid receptor inhibition has shown beneficial effects against kidney injury induced by hypertension in animal models, including the stroke-prone spontaneously hypertensive rat, 72 the radiation injury hypertensive model 73 and spontaneously hypertensive rats.…”

The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis

“…Eplerenone (Inspra, Pfizer Pharma PFE GmbH, Berlin, Germany) was given p.o. (100 mg·kg −1 bw) once per day dissolved in 5 g hazelnut spread (Youcef et al ., ; Fujihara et al ., ; Yan et al ., ). Control animals were treated similarly with 5 g hazelnut spread.…”

Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

“…However, a beneficial effect on collagen deposition and macrophage infiltration was observed only when it was given together with losartan, possibly through a better antihypertensive effect. 56 Given that a common feature in the aforementioned studies is the positive effect of MRAs on proteinuria, MR inhibition was thought likely to be acting through an effect on podocyte health, therefore maintaining the glomerular filtration barrier. In the Dahl salt hypertensive rat model, eplerenone had a modest effect on reducing blood pressure, but it reduced podocyte damage and effacement and delayed the progression of proteinuria and glomerulosclerosis.…”