Abstract: FR-PO717

Metformin Ameliorates the Progressive Nephritis of an Experimental Alport Syndrome Mouse Model

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Omachi, Kohei, Kumamoto University, Kumamoto, Japan
  • Kaseda, Shota, Kumamoto University, Kumamoto, Japan
  • Yokota, Tsubasa, Kumamoto University, Kumamoto, Japan
  • Suico, Mary Ann, Kumamoto University, Kumamoto, Japan
  • Shuto, Tsuyoshi, Kumamoto University, Kumamoto, Japan
  • Kai, Hirofumi, Kumamoto University, Kumamoto, Japan
Background

Alport syndrome (AS) is a hereditary glomerular disease for which renin-angiotensin-aldosterone (RAAS) inhibitor is primarily prescribed. Although RAAS inhibitor is effective for proteinuria, it is not a cure for AS and most patients develop end-stage renal disease. Thus, there is a need to explore other therapeutic avenues. Here, we show the occurrence of metabolic disorder in the glomeruli of Alport mouse model, and that metformin, an anti-diabetic agent, ameliorated the progressive nephritis in AS mice.

Methods

To clarify the molecular underpinning of AS, glomerular samples were collected from 12-week-old wild type and Alport mice (B6, Col4a5 G5X), and global protein expression analysis was performed by LC-MS/MS. To improve the metabolic dysregulation, Alport mice were treated with metformin (6-11w: 5 mg/mL,12-20w: 2.5mg/mL, po) or vehicle from 6 to 20 weeks old. RAS inhibitor losartan (6-11w: 250µg/mL,12-20w: 125µg/mL, po) was used as positive control. Urine samples were collected once every two weeks. Plasma and kidney tissue samples were collected from 20-week-old mice and histological analysis (PAM and Masson trichrome staining) was performed. Expression of genes associated with kidney injury (Lysozyme, Kim1), pro-inflammatory cytokines (Il-6, Il-1b, KC) and pro-fibrotic factors (Tgfb, Mmp9/12) were assessed by qRT-PCR.

Results

Proteomics analysis revealed dysregulation of mitochondrial energy pathway (COX I biogenesis, respiratory electron transport, and ATP synthesis) in addition to already known glomerular damage-associated pathway (nephrin interaction and laminin interaction). Metformin suppressed proteinuria. Although the reduction of proteinuria was lower than losartan, metformin reduced the expression of pro-inflammatory cytokines and pro-fibrotic genes better than losartan. Correlated with these results, metformin suppressed fibrotic area and macrophage invasion histologically.

Conclusion

This study revealed that metabolic disorder occurs in Alport glomerulus and that metformin suppressed progressive nephritis. Metformin is an inexpensive drug that is applicable to pediatric patients. With these findings, metformin could be considered as a novel option for AS therapy.

Funding

  • Private Foundation Support