Kidney Week

Abstract: FR-PO0321

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

Session Information

• Diabetic Kidney Disease: Basic and Translational Science Advances - 1
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Tatsugawa, Rie, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Rie Tatsugawa, MD

• Kidokoro, Kengo, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Kengo Kidokoro, MD, PhD

• Wada, Yoshihisa, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Yoshihisa Wada, MD

• Wada, Masafumi, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Masafumi Wada, MD

• Takasu, Masanobu, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Masanobu Takasu, MD

• Kishi, Seiji, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Seiji Kishi, MD, PhD

• Nagasu, Hajime, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Hajime Nagasu, MD, PhD

• Sasaki, Tamaki, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Tamaki Sasaki, MD, PhD

• Kashihara, Naoki, Kawasaki Ika Daigaku, Kurashiki, Okayama Prefecture, Japan

Naoki Kashihara, MD, PhD

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

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025jkbjq64a