CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

Abstract

The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury.

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

“…Esaxerenone is a nonsteroidal mineralocorticoid receptor blocker that has exhibited kidney protective effects superior to eplerenone in preclinical trials (16,17). This study showed that esaxerenone as add-on therapy to RASi in Japanese participants for 12 weeks reduced UACR by approximately one half in a dose-dependent manner.…”

“…Esaxerenone (CS-3150; Daiichi-Sankyo), a nonsteroidal mineralocorticoid receptor blocker, showed kidney protective effects in preclinical studies and may be added to existing treatments for patients with diabetic kidney disease (16,17). In a phase 1 study, the safety of a single dose and multiple doses of esaxerenone was confirmed in healthy Japanese subjects (18).…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

“…2015 b ). Furthermore, esaxerenone not only prevented but also ameliorated hypertension and renal injury in DOCA rats (Arai et al 2016). …”

Vascular and inflammatory mineralocorticoid receptors in kidney disease

“…67 The effect of endothelial EnNaC deletion in promoting better recovery from hypoxia may be related to the increased generation of NO, thus preventing sustained vasoconstriction and allowing better kidney perfusion. [77][78][79] In a similar model, which uses DOCA administration instead of aldosterone, specific MR deletion in the endothelium ameliorated cardiac remodelling, but not renal injury, suggesting that the MR in the endothelium is not directly involved in this type of kidney injury and that other cell types in which the MR is expressed, such as inflammatory smooth muscle cells, must be involved. 67 Kidney fibrosis has been widely studied in the 5/6 nephrectomy model, in which aldosterone has shown to play a key role.…”

“…76 A similar benefit was observed in this model of aldosterone-induced kidney injury using novel non-steroidal MRAs, such as SM-368229 CS-3150 or AZD9977. [77][78][79] In a similar model, which uses DOCA administration instead of aldosterone, specific MR deletion in the endothelium ameliorated cardiac remodelling, but not renal injury, suggesting that the MR in the endothelium is not directly involved in this type of kidney injury and that other cell types in which the MR is expressed, such as inflammatory smooth muscle cells, must be involved. 52 The extent of MR-induced kidney injury differs between the various models of hypertension.…”