Impact of the Nonsteroidal Mineralocorticoid Receptor Blocker Esaxerenone on Glomerular Hemodynamics in Diabetic Kidney Disease

Background: The FIDELIO-DKD trial showed finerenone, a non-steroidal selective mineralocorticoid receptor blocker (MRB), reduced kidney failure and disease progression in diabetic kidney disease (DKD). Esaxerenone, another non-steroidal MRB, decreased albuminuria in hypertensive patients with type 2 diabetes in the ESAX-DN study. However, the mechanisms behind these effects remain unclear. A decrease in eGFR is observed from the early phase of MRB treatment, and eGFR increases again upon discontinuation. This suggests that MR activity functionally regulates GFR and is likely involved in the pathogenesis of glomerular hyperfiltration in DKD. We hypothesize that MR activation induces glomerular hyperfiltration in DKD by diminishing tubuloglomerular feedback (TGF) through a NO-mediated mechanism in macula densa (MD). We examined the suppressive effects of MRB on glomerular hyperfiltration and elucidated its underlying mechanisms. Methods: Male Sprague-Dawley (SD) ratswere administered aldosterone (1.0 μg/h via osmotic pumps) and esaxerenone orally (3 mg/kg/day). After three days, single nephron GFR (SNGFR), afferent/efferent arteriolar diameters, and glomerular volume were measured using a multiphoton microscope. The effects of esaxerenone on glomerular hemodynamics were also assessed in male db/db mice (type 2 diabetes) and control db/+m mice, both fed a high-salt diet (3% NaCl) and treated with esaxerenone (3 mg/kg/day). SNGFR and arteriolar diameters were measured in vivo. An adenosine A1 receptor (A1aR) antagonist (1 mg/kg) was used to explore TGF mechanisms. Results: Aldosterone increased afferent arteriolar diameter and SNGFR in SD rats, indicating glomerular hyperfiltration. Esaxerenone mitigated these changes, confirming the role of MR activation in GFR regulation. Db/db mice exhibited higher urinary albumin levels and SNGFR compared to control. Esaxerenone reduced albumin levels and glomerular hyperfiltration. Combining esaxerenone with the A1aR antagonist diminished the inhibitory effect of esaxerenone on glomerular hyperfiltration. Conclusion: In DKD, MR activation is implicated in glomerular hyperfiltration, likely through a mechanism mediated by TGF. The impact of MR activation in maculodensin on TGF is currently under investigation. Funding: Commercial Support - Daiichi Sankyo Company