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Abstract: TH-OR081

Extracellular Matrix Component Mediated DDR1 Activation Causes Podocyte Lipotoxicity and Progression of Renal Disease in Alport Syndrome

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix


  • Kim, Jin Ju, University of Miami, Miami, Florida, United States
  • Molina David, Judith T., University of Miami, Miami, Florida, United States
  • Wilbon, Sydney S., University of Miami, Miami, Florida, United States
  • Varona Santos, Javier T., University of Miami, Miami, Florida, United States
  • Prunotto, Marco, F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • Merscher, Sandra M., University of Miami, Miami, Florida, United States
  • Miner, Jeffrey H., Washington University School of Medicine, St. Louis, Missouri, United States
  • Fornoni, Alessia, University of Miami, Miami, Florida, United States

The GBM is primarily composed of laminin and Collagen type IV. De novo production of the collagen type I (Col I) has been observed in mouse models of Alport Syndrome (AS mice, Col4a3KO). Discoidin domain receptor 1 (DDR1) is activated by collagens. Deletion of DDR1 in AS mice was shown to improve survival and renal function. We reported that lipid (LD) accumulation in mice with AS contributes to disease progression. However, how DDR1 activation by aberrant collagen production may contribute to podocyte lipotoxic injury and proteinuria in AS is poorly understood


AS mice were obtained from the Jackson Laboratory for the determination of DDR1 phosphorylation and for the treatment with ezetimibe (EZ) or in combination with Ramipril (RM). Following Col I treatment (50ug/mL, 18hrs), podocyte lipid content was determined by BODIPY 493/503 and Cell Mask Blue staining. Free fatty acid (FFA) uptake was assessed using a fluorometric kit.


We demonstrate that pDDR1 is increased in kidney cortexes of AS mice and pDDR1 levels correlate with blood urine nitrogen (BUN, R2 =0.7, p<0.01). In vitro, DDR1 is activated by Col I in human podocytes. Increased LD accumulation (p<0.05), FFA uptake (p<0.01) and triglyceride (TG) levels (p<0.01) were observed in Col I treated podocytes. DDR1 interacts with CD36, a protein involved in FFA uptake. Podocytes transfected with DDR1(DA) showed increased FFA uptake and TG level compared to cells transfected with WT and DDR1(DN) (p<0.05). A similar phenotype was observed in immortalized podocytes isolated from AS mice. We show that EZ interferes with the interaction between CD36 and DDR1 in HEK 293 cells. In vivo, administration of EZ or RM to AS mice preserves renal function. While EZ restores normal renal triglyceride content, we discovered an unexpected effect of RM, which lowered renal cholesterol content. Interestingly, we also observed an additive effect on renal fibrosis when a combination of EZ and RM was used compared to when either of the drugs was given to AS mice.


Our study suggests that Col I/DDR1-mediated lipotoxicity may represent a novel mechanism leading to podocyte injury in AS that is amenable to therapeutic intervention through a repurposing strategy of EZ.


  • NIDDK Support