Vascular and inflammatory mineralocorticoid receptors in kidney disease

Barrera‐Chimal, Jonatan; Jaisser, Frédéric

doi:10.1111/apha.13390

Cited by 7 publications

(4 citation statements)

References 93 publications

(215 reference statements)

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“…The antihypertensive effect was also greater among patients concomitantly taking ACE-I/ARB. MRAs could result in sustained improvement of fibrosis of various organs throughout the body [20][21][22][23][24], and our findings suggest that apararenone could improve DN. Thus, apararenone would be expected to improve fibrotic disease in the liver and other organs.…”

Section: Discussionsupporting

confidence: 52%

Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose–response study and open-label extension study

et al. 2020

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Background We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). Methods The study had two parts: a dose–response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). Results In the dose–response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. Conclusion The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. Clinical trial registration NCT02517320 (dose–response study) and NCT02676401 (extension study)

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Section: Discussionsupporting

confidence: 52%

Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose–response study and open-label extension study

et al. 2020

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“…Beyond the distal tubular cells, MR is also distributed in the endothelial cells, smooth muscle, mesangial and inflammatory cells, podocytes, and fibroblasts. 42 MR antagonists (MRAs) exert vital effect on renal pathophysiology which has been summarized in a recent elegant review. 43 Multiple MRAs are currently being tested in preclinical studies and clinical trials to confirm their therapeutic actions in CKD.…”

Section: Mineralocorticoid Receptor (Mr)mentioning

confidence: 99%

Nuclear receptors in renal health and disease

et al. 2022

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Summary As a major social and economic burden for the healthcare system, kidney diseases contribute to the constant increase of worldwide deaths. A deeper understanding of the underlying mechanisms governing the etiology, development and progression of kidney diseases may help to identify potential therapeutic targets. As a superfamily of ligand-dependent transcription factors, nuclear receptors (NRs) are critical for the maintenance of normal renal function and their dysfunction is associated with a variety of kidney diseases. Increasing evidence suggests that ligands for NRs protect patients from renal ischemia/reperfusion (I/R) injury, drug-induced acute kidney injury (AKI), diabetic nephropathy (DN), renal fibrosis and kidney cancers. In the past decade, some breakthroughs have been made for the translation of NR ligands into clinical use. This review summarizes the current understanding of several important NRs in renal physiology and pathophysiology and discusses recent findings and applications of NR ligands in the management of kidney diseases.

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“…Interestingly, mineralocorticoid receptors (MR) also induce oxidative injury. In the last decade, cumulative evidence has emerged that mineralocorticoid receptors contribute to the progress of AKI to CKD, and that oxidative injury may play a prominent role 7 . In addition to that, MR mediates vascular inflammation, calcification and thus increase vascular stiffness and induce hypertension; factors which promote the development of CKD.…”

mentioning

confidence: 99%