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Abstract: TH-PO785

Elucidation of the Molecular Mechanism of Albuminuria Improvement by Nonsteroidal Mineralocorticoid Receptor (MR) Antagonists Focusing on Podocyte Calcium (Ca2+) Dynamics

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Iwakura, Tsukasa, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan
  • Kidokoro, Kengo, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan
  • Kishi, Seiji, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan
  • Nagasu, Hajime, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan
  • Kashihara, Naoki, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan
  • Sasaki, Tamaki, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan
Background

MR activation in podocytes has been linked to the progression of glomerular and podocyte injuries in diabetic kidney disease (DKD). In the FIDELIO-DKD study, non-steroidal MR inhibitors showed a significant reduction in the development of renal outcomes compared to placebo. However, there are still many unknown aspects regarding MR activation in DKD. Transient Receptor Potential Canonical (TRPC)s, a Ca2+ channel in podocytes, has been implicated in various kidney diseases, including hereditary nephrotic syndrome. We hypothesized that increased TRPC activity and expression due to MR activation in podocytes contribute to glomerular damage in DKD. We investigated the molecular mechanism of finerenone's effect on improving albuminuria in DKD.

Methods

C57BL/6 mice (control) and diabetic Akita mice (Akita) were used in the study. Four groups were created: Control-Nx (Nx; one nephrectomized), Control-Nx+HS (high salt diet), Akita-Nx+HS, and Akita-Nx+HS+finerenone. The mice were sacrificed at 17 weeks of age, and specimens and tissues were analyzed. In vivo imaging using a two-photon laser microscope was performed to confirm changes in albumin leakage from glomeruli. Additionally, cultured podocytes were used to assess the effect of aldosterone (Aldo) stimulation on TRPC5 expression, reactive oxygen species (ROS) production, Ca2+ influx, and actin rearrangement. Podocin-GCaMP5/tdTomato mice, which specifically express the calcium sensor protein GCaMP in podocytes, were used to study the effect of Aldo stimulation on Ca2+ influx.

Results

The Akita-Nx+HS group exhibited abnormal podocyte morphology and significantly increased albuminuria. Increased intraglomerular ROS production was observed, along with clear albumin leakage from glomeruli. In cultured podocytes, Aldo stimulation induced increased TRPC5 protein expression, ROS production, Ca2+ influx, and actin rearrangement. Similar Ca2+ influx was observed in Podocin-GCaMP5/tdTomato mice. These changes were ameliorated by MR and TRPC5 inhibitors.

Conclusion

The study demonstrated that MR activation in podocytes contributes to glomerular damage in DKD through increased TRPC5 channel expression and activity. MR inhibitors like finerenone improve podocyte Ca2+ dynamics and reduce damage in DKD.

Funding

  • Commercial Support – Bayer