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Abstract: FR-OR054

The NGAL-Macrophage Therapy Improves Diabetic Kidney Disease in db/db Mice by Induction of PI3K/Akt Pathway

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Guiteras, Roser, IDIBELL, Barcelona, Spain
  • Sola, Anna, IDIBELL, Barcelona, Spain
  • Manonelles, Anna, Hospital Universitari de Bellvitge, Barcelona, Spain
  • Hotter, Georgina, IIBB-CSIC, Barcelona, Spain
  • Cruzado, Josep M., Hospital Universitari de Bellvitge, Barcelona, Spain

Group or Team Name

  • Nephrology and Renal Experimental Transplantation, Institut d’Investigació biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
Background

Alternatively activated macrophages (M2) have regenerative properties and shown promise as cell therapy in chronic kidney disease. However, M2 plasticity is one of the major hurdles to overcome. Genetically modified macrophages stabilized by neutrophil gelatinase-associated lipocalin (NGAL) are able to preserve in stable manner their M2 phenotype. Nowadays, little is known about M2 macrophage effects in diabetic kidney disease (DKD). The aim of the study was to investigate the therapeutic effect of both bone marrow-derived M2 (BM-ØM2) and Ø-NGAL macrophages in the db/db mice

Methods

Seventeen wk-old mice with established DKD were divided into five treatment groups with their controls: D+BM-ØM2; D+Ø-BM; D+Ø-NGAL; D+Ø-RAW; D+SHAM and non-diabetic (ND) (db/- and C57bl/6J) animals. We infused 1x106 macrophages twice, at baseline and 2 weeks thereafter. Blood, urine samples and kidney tissue were collected. To further ascertain the mechanism by which NGAL macrophage cell therapy is involved in epithelial kidney repair, we co-cultured renal epithelial cells and macrophages in vitro. We assessed epithelial proliferation, repair and epithelial phenotype integrity.

Results

BM-ØM2 did not show any therapeutic effect whereas Ø-NGAL significantly reduced albuminuria and renal fibrosis in db/db mice. The Ø-NGAL therapy increased the anti-inflammatory IL-10 and reduced some pro-inflammatory cytokines, reduced the proportion of M1 glomerular macrophages and podocyte loss and was associated with a significant decrease of renal TGF-β1. Furthermore, we demonstrated in vitro that NGAL overexpression in macrophages enhanced epithelial markers and healthy epithelial phenotype through the induction of PI3K/Akt pathway. In addition, NGAL activated proliferation markers such as Ki67 and PCNA through the inhibition of PPAR-γ.

Conclusion

Overall, our study provides evidence that NGAL macrophage cell therapy has therapeutic effects on DKD. NGAL acts as a mediator and is a crucial player reducing inflammation, fibrosis and promoting epithelial proliferation.

Funding

  • Private Foundation Support