Balcinrenone Shows a Unique Regulation of Potassium Excretion in Streptozotocin-induced Diabetes in Male Mice.

Abstract

Patients with diabetes are disproportionately affected by cardiovascular and kidney disease. Mineralocorticoid receptor (MR) antagonists show organ protection against cardiovascular and renal injury; however, major side effects including hyperkalemia and reduced renal function limit their use in individuals with diabetic complications. The nonsteroidal MR modulator balcinrenone may offer end-organ protection with fewer side effects. We compared responses to balcinrenone and eplerenone delivered from 8 weeks postinduction of streptozotocin (STZ)-induced type 1 diabetes in male mice. RNA sequencing revealed diabetes induced modulation of immune function, and metabolic and vascular targets in the kidney, which were similarly attenuated by balcinrenone or eplerenone treatment. Urine K+ excretion was lower following eplerenone treatment, but not balcinrenone treatment, compared to diabetes without treatment. We identified a 5.90-fold increase in the expression of K+ transporter G protein-activated inward rectifier potassium channel 1 in eplerenone- but not balcinrenone-treated diabetic mice. Balcinrenone and eplerenone similarly attenuated the diabetes-induced reduction in peak E-wave/A-wave velocity compared to mice without treatment at 15 weeks post-STZ. Gene markers of cardiac injury, B-type natriuretic peptide, and beta-myosin heavy chain protein were higher in diabetic vs nondiabetic left ventricles (LVs). Conversely, gene expression of Ca2+ ion channel subunits, voltage-dependent L type, calcium channel subunit alpha 1C, and ryanodine receptor 2 in LV was lower in diabetic but not eplerenone- or balcinrenone-treated diabetic mice. Although balcinrenone and eplerenone similarly modified cardiac changes, potassium excretion was greater with balcinrenone, consistent with a reduced risk of hyperklemia with the nonsteroidal MR modulator.Copyright © The Author(s) 2026. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.