Effects of Non-steroidal Mineralocorticoid Receptor Blocker Esaxerenone on Glomerular Hemodynamics in type 2 Diabetic Kidney Disease

The non-steroidal selective mineralocorticoid receptor blocker (nsMRB) finerenone has demonstrated renoprotective effects in patients with type 2 diabetes and chronic kidney disease (CKD) (FIDELIO-DKD study). Similarly, the nsMRB esaxerenone (Esax) significantly reduced albuminuria compared with placebo in a phase III trial involving early diabetic kidney disease (DKD), suggesting renoprotective effects comparable to finerenone (ESAX-DN study). However, the molecular mechanisms underlying the renoprotective and albuminuria-lowering effects of nsMRBs remain unclear. After nsMRB administration, a transient decline in estimated glomerular filtration rate (eGFR) is observed, followed by recovery upon withdrawal, similar to SGLT2 inhibitors. This indicates that MR activity functionally regulates GFR and may contribute to glomerular hyperfiltration in DKD. Few studies, however, have directly examined the link between MR activity and glomerular hemodynamics. The macula densa (MD) plays a central role in tubuloglomerular feedback (TGF). MR activation in MD cells is thought to attenuate TGF through nitric oxide (NO), though mechanisms are not fully defined. We hypothesized that MR activation in MD cells contributes to glomerular hyperfiltration in DKD and investigated this using in vivo imaging and a newly established MD cell line (MDgeo).

To assess MR activation–induced hemodynamic changes, male Sprague–Dawley rats (8–10 weeks, n = 3–4) received aldosterone (Aldo; 1.0 μg/h, 3 days) and/or Esax (3 mg/kg/day, 3 days). In vivo two-photon microscopy measured single-nephron GFR (SNGFR), afferent (AA) and efferent arteriole (EA) diameters, and glomerular volume. For DKD, male db/db mice (n = 8) were used with db/+m controls. Mice were fed a high-salt diet (3% NaCl) and treated with Esax (3 mg/kg/day) for 8 weeks. Blood pressure, heart rate, body weight, urinary albumin, and renal histology were evaluated. SNGFR and AA/EA diameters were assessed by in vivo imaging. To examine adenosine involvement, an adenosine A1 receptor (A1aR) antagonist was administered. MDgeo cells were stimulated with Aldo or treated with Esax, and adenosine and NO levels in supernatants and NKCC2 membrane localization were analyzed.

In rats, Aldo significantly dilated afferent arterioles (Control: 16.73 ± 0.89 μm vs. Aldo: 22.48 ± 1.09 μm, P < 0.01) and increased SNGFR (Control: 19.72 ± 1.56 nl/min vs. Aldo: 28.69 ± 1.54 nl/min, P < 0.01). In db/db mice, albuminuria (Control: 0.037 ± 0.004 mg/gCr vs. db/db: 1.023 ± 0.156 mg/gCr, P < 0.01), afferent diameter (Control: 15.24 ± 0.79 μm vs. db/db: 21.19 ± 0.89 μm, P < 0.01), and SNGFR (Control: 8.86 ± 0.58 nl/min vs. db/db: 11.42 ± 0.59 nl/min, P < 0.01) were increased, but Esax attenuated these changes. A1aR blockade blunted Esax’s suppressive effect on hyperfiltration. In MDgeo cells, Aldo increased NO production, which was suppressed by Esax. Under Aldo stimulation, adenosine secretion rose with Esax or nNOS inhibition. Aldo reduced NKCC2 membrane expression, while Esax and nNOS inhibition restored it. In vivo, NKCC2 expression in macula densa cells was diminished in db/db mice but preserved with Esax treatment. MR activity in MD cells thus regulates TGF responsiveness via the nNOS–NO pathway.

Correction of glomerular hyperfiltration in DKD by Esax involved the adenosine–A1aR pathway within TGF. MR activity in MD cells contributes to TGF regulation and may drive glomerular hyperfiltration in DKD.