Abstract for presentation at Australia and New Zealand Society of Nephrology Annual Scientific Conference

** Bone marrow-derived endothelial-myofibroblast transdifferentiation in the progression of renal fibrosis

  • Dr Jinhua Li, Monash University, Australia
  • Ms Naomi Campanale, Monash Immunology and Stem Cell Laboratories, Australia
  • Dr James Deane, Monash University, Australia
  • John Bertram, Monash University, Australia
  • Sharon Ricardo, Monash University, Australia

    • Recent evidence suggests that bone marrow (BM)-derived cells may integrate into the kidney giving rise to functional renal cell types including endothelial and epithelial cells, and myofibroblasts. However, the source of BM cells that are capable of transdifferentiating into renal fibroblasts or myofibroblasts remains unclear.
    Using chimeric mice transplanted with enhanced green fluorescent protein (EGFP)-expressing BM we demonstrate that the number of BM-derived myofibroblasts coincided with the development of fibrosis in a mouse adriamycin (ADR)-induced nephrosis model. Six weeks after ADR injection, the BM contributed to more than 30% of renal α-smooth muscle actin (+) (α-SMA+) interstitial myofibroblasts. BM-derived cells were also observed to differentiate into proximal tubular capillary (PTC) endothelial cells. Furthermore, these BM-derived cells contributed to the progression of renal interstitial fibrosis via endothelial-mesenchymal transdifferentiation where serial confocal microscopy identified the presence of triple immunolabelled von Willebrand factor (vWF)(+)/α-SMA (+)/EGFP(+) cells in ADR recipient kidneys. p38 MAPK and TGFβ1/Smad2 signaling pathways were activated in BM-derived PTC endothelial cells and BM-derived myofibroblasts. Inhibition of the p38 MAPK and TGF-β1/Smad signaling pathways enhanced PTC repair by decreasing endothelial-myofibroblast transdifferentiation leading to structural and functional renal recovery and the attenuation of renal interstitial fibrosis.
    These results indicate that BM-derived cells contribute to renal fibrosis through the process of endothelial-mesenchymal transdifferentiation and that the p38 MAPK and TGFβ1/Smad2 signaling pathways play important roles in this process. This study raises the possibility that novel therapies to prevent or retard the progression of ESRD could target BM-derived endothelial-mesenchymal transdifferentiation that accelerates renal interstitial fibrosis.

    Conference Organiser - ICMS Pty Ltd