Potential Impact of Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiovascular Disease.

Inappropriate mineralocorticoid receptor (MR) activation in different cardiovascular cell types has deleterious effects on cardiac remodeling and function. Therefore, MR inhibition is a crucial pharmacological strategy to overcome cardiovascular dysfunction. Despite efficient blockade of MR with steroidal MR antagonists (MRAs), their clinical application is unsatisfactory due to the adverse effects. Newer non-steroidal MRAs with greater potency could be suitable for clinical application, especially in patients with type 2 diabetes mellitus and chronic kidney disease. Although clinical evidence has shown the beneficial effects of non-steroidal MRAs on cardiovascular outcomes in patients with heart failure with reduced ejection fraction, clinical trials are ongoing to evaluate the efficacy of heart failure with preserved ejection fraction. Therefore, comparative pharmacological characterization of non-steroidal MRAs over classic steroidal MRAs is crucial. Here, we summarize the pre-clinical evidence of non-steroidal MRAs, which suggests an improvement in cardiac dysfunction, as well as the underlying molecular mechanisms in animal models mimicking different clinical conditions. In addition, we discuss up-to-date information from clinical trials regarding the beneficial effects of non-steroidal MRAs on meaningful cardiovascular outcomes. Both pre-clinical and clinical evidence support treatment with non-steroidal MRAs in patients with cardiovascular disease.

Association of Antihypertensive Effects of Esaxerenone with the Internal Sodium Balance in Dahl Salt-Sensitive Hypertensive Rats.

BACKGROUND: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). OBJECTIVE: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. METHODS: In the different experimental setups, we evaluated BP by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a low-salt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. RESULTS: HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone- and furosemide-treated rats compared with their HSD-fed counterparts. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. Histological evaluation showed that esaxerenone, but not furosemide, treatment attenuated glomerulosclerosis, tubulointerstitial fibrosis, and urinary protein excretion induced by high salt loading. CONCLUSIONS: Collectively, these findings suggest that an esaxerenone treatment-induced reduction in BP and renoprotection are associated with body sodium homeostasis in salt-loaded DSS rats.

Cardioprotective Effects of a Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, in Dahl Salt-Sensitive Hypertensive Rats.

We investigated the effects of esaxerenone, a novel, nonsteroidal, and selective mineralocorticoid receptor blocker, on cardiac function in Dahl salt-sensitive (DSS) rats. We provided 6-week-old DSS rats a high-salt diet (HSD, 8% NaCl). Following six weeks of HSD feeding (establishment of cardiac hypertrophy), we divided the animals into the following two groups: HSD or HSD + esaxerenone (0.001%, w/w). In survival study, all HSD-fed animals died by 24 weeks of age, whereas the esaxerenone-treated HSD-fed animals showed significantly improved survival. We used the same protocol with a separate set of animals to evaluate the cardiac function by echocardiography after four weeks of treatment. The results showed that HSD-fed animals developed cardiac dysfunction as evidenced by reduced stroke volume, ejection fraction, and cardiac output. Importantly, esaxerenone treatment decreased the worsening of cardiac dysfunction concomitant with a significantly reduced level of systolic blood pressure. In addition, treatment with esaxerenone in HSD-fed DSS rats caused a reduced level of cardiac remodeling as well as fibrosis. Furthermore, inflammation and oxidative stress were significantly reduced. These data indicate that esaxerenone has the potential to mitigate cardiac dysfunction in salt-induced myocardial injury in rats.

Possible contribution of phosphate to the pathogenesis of chronic kidney disease in dolphins.

This study aimed to investigate whether phosphate contributes to the pathogenesis of chronic kidney disease (CKD) in dolphins. Renal necropsy tissue of an aged captive dolphin was analyzed and in vitro experiments using cultured immortalized dolphin proximal tubular (DolKT-1) cells were performed. An older dolphin in captivity died of myocarditis, but its renal function was within the normal range until shortly before death. In renal necropsy tissue, obvious glomerular and tubulointerstitial changes were not observed except for renal infarction resulting from myocarditis. However, a computed tomography scan showed medullary calcification in reniculi. Micro area X-ray diffractometry and infrared absorption spectrometry showed that the calcified areas were primarily composed of hydroxyapatite. In vitro experiments showed that treatment with both phosphate and calciprotein particles (CPPs) resulted in cell viability loss and lactate dehydrogenase release in DolKT-1 cells. However, treatment with magnesium markedly attenuated this cellular injury induced by phosphate, but not by CPPs. Magnesium dose-dependently decreased CPP formation. These data support the hypothesis that continuous exposure to high phosphate contributes to the progression of CKD in captive-aged dolphins. Our data also suggest that phosphate-induced renal injury is mediated by CPP formation in dolphins, and it is attenuated by magnesium administration.

Renoprotective Effects of Mangiferin: Pharmacological Advances and Future Perspectives.

Both acute and chronic kidney diseases substantially contribute to the morbidities and mortality of patients worldwide. The existing therapeutics, which are mostly developed from synthetic sources, present some unexpected effects in patients, provoking researchers to explore potential novel alternatives. Natural products that have protective effects against various renal pathologies could be potential drug candidates for kidney diseases. Mangiferin is a natural polyphenol predominantly isolated from Mangifera indica and possesses multiple health benefits against various human ailments, including kidney disease. The main objective of this review is to update the renoprotective potentials of mangiferin with underlying molecular pharmacology and to highlight the recent development of mangiferin-based therapeutics toward kidney problems. Literature published over the past decade suggests that treatment with mangiferin attenuates renal inflammation and oxidative stress, improves interstitial fibrosis and renal dysfunction, and ameliorates structural alteration in the kidney. Therefore, mangiferin could be used as a multi-target therapeutic candidate to treat renal diseases. Although mangiferin-loaded nanoparticles have shown therapeutic promise against various human diseases, there is limited information on the targeted delivery of mangiferin in the kidney. Further research is required to gain insight into the molecular pharmacology of mangiferin targeting kidney diseases and translate the preclinical results into clinical use.