PROTECTIVE ROLE OF FINERENONE AGAINST PODOCYTE INJURY THROUGH MR–TRPC PATHWAY INHIBITION IN DIABETIC KIDNEY DISEASE

Finerenone, a non-steroidal selective mineralocorticoid receptor antagonist (nsMRA), has demonstrated renoprotective effects in patients with chronic kidney disease (CKD) and type 2 diabetes, as shown in the FIDELIO-DKD study. However, the underlying physiological mechanism responsible for its albuminuria-reducing effect remains incompletely understood. Animal studies have reported that excessive activation of mineralocorticoid receptors (MRs) in glomerular cells contributes to the progression of diabetic kidney disease (DKD) and albuminuria, and is also associated with metabolic abnormalities such as hypertension, heart failure, and type 2 diabetes. Mechanistically, transient receptor potential canonical (TRPC) channels—particularly TRPC5 and TRPC6—have been implicated in increased Ca²⁺ influx into podocyte foot processes, leading to cytoskeletal remodeling and subsequent albuminuria. We hypothesized that MR inhibition protects glomerular epithelial cells (podocytes) by limiting excessive Ca²⁺ influx mediated by TRPC5, thereby reducing albuminuria, and tested this hypothesis.

C57BL/6 (control) and diabetic Ins2⁺/Akita mice underwent unilateral nephrectomy (UNx) at 8 weeks of age. Mice were divided into groups fed a normal-salt (0.5% NaCl), high-salt (3% NaCl; HS), or finerenone-treated diet (Fine; 10 mg/kg/day for 8 weeks). The groups were: UNx-Control, UNx-HS Control, UNx-HS Ins2⁺/Akita, and UNx-HS Ins2⁺/Akita + Fine. Albuminuria, glomerular morphology (PAS staining, EM), and reactive oxygen species (ROS) production were assessed. Single-nephron glomerular filtration rate (SNGFR) was measured by two-photon microscopy. Protein expression of Sgk1 and TRPC5 in kidney and isolated glomeruli was evaluated by Western blotting. In cultured podocytes, intracellular Ca²⁺, TRPC5 and Sgk1 expression, and F-actin remodeling induced by aldosterone (Aldo) were analyzed, comparing finerenone and the TRPC5 inhibitor AC1903. Diabetes was also induced in Podocin-GCaMP5/tdTomato mice with streptozotocin (STZ; 50 mg/kg for 5 days) to visualize Ca²⁺ dynamics in vivo and ex vivo.

The UNx-HS-Ins2⁺/Akita group showed marked increases in albuminuria, foot process width, and SNGFR. Finerenone significantly reduced albuminuria and restored foot process width. SNGFR also decreased, while systolic blood pressure remained unchanged, suggesting a BP-independent effect. Intraglomerular ROS and Sgk1/TRPC5 expression were elevated in diabetic mice but suppressed by finerenone. In cultured podocytes, Aldo increased TRPC5 and Sgk1, intracellular Ca²⁺, ROS, and F-actin remodeling, all of which were attenuated by finerenone or AC1903, with stronger effects for finerenone. In STZ-diabetic Podocin-GCaMP5 mice, podocyte Ca²⁺ elevation was reduced by either drug and further decreased by their combination, accompanied by improved albuminuria and SNGFR.

Finerenone ameliorated albuminuria and glomerular hyperfiltration in diabetic nephropathy by suppressing podocyte Ca²⁺ influx and ROS production. Its renoprotective effects likely involve both cytoprotection via MR–TRPC5 signaling inhibition and MR-dependent hemodynamic modulation.