Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease.

The steroidal mineralocorticoid receptor (MR) antagonists, spironolactone and eplerenone, decrease blood pressure, and attenuate the progression of chronic kidney disease (CKD). However, their use is limited by the fear of inducing hyperkalemia, gynecomastia, impotence, and amenorrhea. Esaxerenone is a novel nonsteroidal MR blocker (MRB) that has been recently developed. In vitro studies have revealed that esaxerenone has a high potency and selectivity for MR compared with spironolactone and eplerenone. Further studies have shown that esaxerenone elicits a strong blood pressure-lowering effect in hypertensive animals. Following the results from phase III clinical trials that esaxerenone is an effective and well-tolerated MRB in Japanese hypertensive patients, esaxerenone became clinically available in Japan from May 2019 for hypertensive patients. Thus, esaxerenone is a promising treatment option for patients with hypertension. In addition, both preclinical studies and phase II clinical trials have shown that esaxerenone elicits renoprotection independent of its antihypertensive effect. Recently, a phase III clinical trial (ESAX-DN study) has also demonstrated the safety and efficacy of esaxerenone in patients with type 2 diabetes and microalbuminuria. These data support future clinical development of esaxerenone for the treatment of renal disease.

Effects of an SGLT2 inhibitor on the salt sensitivity of blood pressure and sympathetic nerve activity in a nondiabetic rat model of chronic kidney disease.

The glucose-lowering effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors is reduced in patients with diabetes who have chronic kidney disease (CKD). In the present study, we examined the effect of an SGLT2 inhibitor on the salt sensitivity of blood pressure (BP), circadian rhythm of BP, and sympathetic nerve activity (SNA) in nondiabetic CKD rats. Uninephrectomized Wistar rats were treated with adenine (200 mg/kg/day) for 14 days. After stabilization with a normal-salt diet (NSD, 0.3% NaCl), a high-salt diet (HSD, 8% NaCl) was administered. Mean arterial pressure (MAP) was continuously monitored using a telemetry system. We also analyzed the low frequency (LF) of systolic arterial pressure (SAP), which reflects SNA. In adenine-induced CKD rats, HSD consumption for 5 days significantly increased the mean MAP from 106 ± 2 to 148 ± 3 mmHg. However, MAP was decreased to 96 ± 3 mmHg within 24 h after switching back to a NSD (n = 7). Treatment with an SGLT2 inhibitor, luseogliflozin (10 mg/kg/day, p.o., n = 7), significantly attenuated the HSD-induced elevation of MAP, which was associated with a reduction in LF of SAP. These data suggest that treatment with an SGLT2 inhibitor attenuates the salt sensitivity of BP, which is associated with SNA inhibition in nondiabetic CKD rats.

Lipopolysaccharide induces filtrate leakage from renal tubular lumina into the interstitial space via a proximal tubular Toll-like receptor 4-dependent pathway and limits sensitivity to fluid therapy in mice.

Sustained oliguria during fluid resuscitation represents a perplexing problem in patients undergoing therapy for septic acute kidney injury. Here, we tested whether lipopolysaccharide induces filtrate leakage from the proximal tubular lumen into the interstitium, thus disturbing the recovery of urine output during therapy, such as fluid resuscitation, aiming to restore the glomerular filtration rate. Intravital imaging of the tubular flow rate in the proximal tubules in mice showed that lipopolysaccharide did not change the inflow rate of proximal tubule filtrate, reflecting an unchanged glomerular filtration rate, but significantly reduced the outflow rate, resulting in oliguria. Lipopolysaccharide disrupted tight junctions in proximal tubules and induced both paracellular leakage of filtered molecules and interstitial accumulation of extracellular fluid. These changes were diminished by conditional knockout of Toll-like receptor 4 in the proximal tubules. Importantly, these conditional knockout mice showed increased sensitivity to fluid resuscitation and attenuated acute kidney injury. Thus, lipopolysaccharide induced paracellular leakage of filtrate into the interstitium via a Toll-like receptor 4-dependent mechanism in the proximal tubules of endotoxemic mice. Hence, this leakage might diminish the efficacy of fluid resuscitation aiming to maintain renal hemodynamics and glomerular filtration rate.

The Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Sympathetic Nervous Activity.

The EMPA-REG OUTCOME study revealed that a sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, can remarkably reduce cardiovascular (CV) mortality and heart failure in patients with high-risk type 2 diabetes. Recently, the CANVAS program also showed that canagliflozin, another SGLT2 inhibitor, induces a lower risk of CV events. However, the precise mechanism by which an SGLT2 inhibitor elicits CV protective effects is still unclear. Possible sympathoinhibitory effects of SGLT2 inhibitor have been suggested, as significant blood pressure (BP) reduction, following treatment with an SGLT2 inhibitor, did not induce compensatory changes in heart rate (HR). We have begun to characterize the effects of SGLT2 inhibitor on BP and sympathetic nervous activity (SNA) in salt-treated obese and metabolic syndrome rats, who develop hypertension with an abnormal circadian rhythm of BP, a non-dipper type of hypertension, and do not exhibit a circadian rhythm of SNA. Treatment with SGLT2 inhibitors significantly decreased BP and normalized circadian rhythms of both BP and SNA, but did not change HR; this treatment was also associated with an increase in urinary sodium excretion. Taken together, these data suggest that an SGLT2 inhibitor decreases BP by normalizing the circadian rhythms of BP and SNA, which may be the source of its beneficial effects on CV outcome in high-risk patients with type 2 diabetes. In this review, we briefly summarize the effects of SGLT2 inhibitors on BP and HR, with a special emphasis on SNA.