Esaxerenone Ameliorates Glomerular Hyperfiltration in Diabetic Kidney Disease by Restoring Tubuloglomerular Feedback via Macula Densa MR Blockade

Background: The FIDELIO-DKD trial demonstrated that finerenone, a non-steroidal selective mineralocorticoid receptor blocker (MRB), suppresses kidney failure and disease progression in diabetic kidney disease (DKD). Esaxerenone, another non-steroidal MRB, reduced albuminuria in patients with type 2 diabetes and hypertension in the ESAX-DN trial. However, the mechanisms underlying these effects remain unclear. We hypothesized that MR activation promotes glomerular hyperfiltration in DKD by attenuating tubuloglomerular feedback (TGF). This study aimed to evaluate the suppressive effects of MRB on glomerular hyperfiltration and elucidate the underlying mechanisms. Methods: Male Sprague-Dawley rats were administered aldosterone (1.0 μg/h via osmotic pump) and esaxerenone (3 mg/kg/day orally). After 3 days, single-nephron GFR (SNGFR), afferent/efferent arteriolar diameters, and glomerular volume were measured using multiphoton microscopy. To examine the effect of esaxerenone on glomerular hemodynamics, male db/db mice (type 2 diabetes model) and control db/+m mice were fed a high-salt diet (3% NaCl) and treated with esaxerenone (3 mg/kg/day). In vivo SNGFR and arteriolar diameters were measured. To investigate the role of TGF, an adenosine A1 receptor antagonist (A1aR antagonist, 1 mg/kg) was used. Furthermore, immortalized MD cells were stimulated with aldosterone (100 nM), esaxerenone (1 μM), or an nNOS inhibitor (10 nM) to assess changes in TGF signaling. Results: In SD rats, aldosterone increased afferent arteriolar diameter and SNGFR, indicating glomerular hyperfiltration, which was attenuated by esaxerenone. In db/db mice, urinary albumin excretion and SNGFR were elevated compared to controls, and these abnormalities were ameliorated by esaxerenone. Co-administration of the A1aR antagonist diminished the inhibitory effect of esaxerenone on glomerular hyperfiltration. In MD cells, MR activation increased NO production and reduced membrane expression of the Na+-K+-2Cl- cotransporter (NKCC2). Conclusion: MR activation in macula densa cells contributes to glomerular hyperfiltration via a TGF-mediated mechanism in DKD. Funding: Commercial Support - DAIICHI SANKYO COMPANY