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Kidney Week

Abstract: FR-PO207

The Mineralocorticoid Receptor Antagonist Finerenone Limits Podocyte Injury in High-Salt Loaded db/db Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hirohama, Daigoro, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
  • Nishimoto, Mitsuhiro, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
  • Ayuzawa, Nobuhiro, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
  • Kawarazaki, Wakako, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
  • Oba, Shigeyoshi, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
  • Marumo, Takeshi, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
  • Fujita, Toshiro, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
Background

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease worldwide; however, the underlying mechanisms have not been fully elucidated. Previously, we identified cross-talk between mineralocorticoid receptor (MR) and the small GTPase Rac1, and found that activation of Rac1-MR pathway is implicated in proteinuric nondiabetic kidney disease (Nat Med 2008, JCI 2011). However, few mouse models of DKD hinder the progress of research on DKD.

Methods

We tried to establish the new mouse model of DKD with typical nodular lesion, in order to evaluate the involvement of Rac1-MR pathway in DKD. We performed uninephrectomy at young age (4-week postpartum) and fed a high-salt (HS) diet for 10 weeks to accelerate kidney damage in type 2 diabetic model of db/db mice. We evaluated urinary albumin excretion and kidney phenotype including Rac1-MR pathway, and the renoprotective role of the MR antagonist Finerenone in this DKD mouse model.

Results

HS loading induced prominent elevation of albuminuria and increased glomerular damage with typical nodular lesion in uninephrectomized db/db mice, which were accompanied by the podocyte injury. In db/m control mice, however, albuminuria and glomerular damage did not increase by uninephrectomy and HS loading. Expressions of active Rac1 and Sgk1, a downstream molecule of MR signaling, in the cortex and isolated glomeruli, were elevated in uninephrectomized and HS-treated db/db mice compared with the treated db/m mice. Of note, glomerular active Rac1 expressions were merged with podocyte specific markers including podocin, suggesting Rac1-MR activation in podocytes of the DKD model mouse. Finerenone inhibited the elevated Sgk1 expressions in glomeruli, associated with the improvement of the glomerular damage and podocyte injury, resulting in the significant reduction of albuminuria.

Conclusion

HS loading induces enhanced MR signaling, podocyte injury, and albuminuria in uninephrectomized db/db mice, which are ameliorated by the treatment of Finerenone, suggesting the involvement of activation of Rac1-MR pathway in the
progression of DKD, and highlighting MR antagonism as a novel approach to treat DKD.

Funding

  • Commercial Support