Genomic and rapid effects of aldosterone: what we know and do not know thus far

Abstract

Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor-the "unknown receptor"-is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone.

p53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction

“…However, p53 activation could also be regulated by a wide variety of posttranslational modifications such as phosphorylation, acetylation, and ubiquitination in addition to its expression level (36). Moreover, the mechanisms of action of aldosterone may be either genomic or nongenomic effects (14). Our previous study showed that aldosterone-induced podocyte apoptosis was inhibited by a mineralocorticoid receptor antagonist, indicating that the response to aldosterone was a classic genomic action (49).…”

Diabetic Kidney Disease: Challenges, Advances, and Opportunities

“…Future studies are required to confirm whether atrasentan has additional renal protective effects on top of the RAS blockades and SGLT2 inhibitors, the new standard care for DKD patients. Mineralocorticoid receptor antagonists (MRA) exert an antifibrotic and anti-inflammatory effect on the kidneys and other target organs like the heart and vessels [77]. Due to significant side effects associated with the first- (spironolactone) and second- (eplerenone) generation MRA, new MRA such as apararenone (also called MT-3995), esaxerenone, and finerenone have a relatively low risk of hyperkalemia.…”

Endolymphatic hydrops induced by different mechanisms responds differentially to spironolactone: a rationale for understanding the diversity of treatment responses in hydropic inner ear disease

“…Exactly how spironolactone interferes with cAMP signaling is not known. An interplay between cAMP and the mineralocorticoid receptor signaling pathways has been described, please see review and references herein [18].…”

“…Thus, different models, read-outs, methods, doses of aldosterone and study designs have been used in the context of spironolactone, aldosterone and the inner ear which may explain some of the contradictory results. One should have in mind that aldosterone is believed to act via the mineralocorticoid receptor as well as via cell surface receptors [18] whereas spironolactone is believed to antagonize the effects induced by the mineralocorticoid receptor only. The exact arrangement and levels of key targets for aldosterone such as the amiloride sensitive Na þ transporter ENaC, NCC and the NaK-ATPase in the inner ear presumably contribute to the impact of altered aldosterone level in different contexts in one or the other direction [19].…”