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Abstract: PO0656

Cell Surface GRP78 Regulates TGF-β1-Mediated Profibrotic Responses via TSP-1 in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Trink, Jackie, McMaster University, Hamilton, Ontario, Canada
  • Ahmed, Usman, McMaster University, Hamilton, Ontario, Canada
  • O'Neil, Kian S., McMaster University, Hamilton, Ontario, Canada
  • Gao, Bo, McMaster University, Hamilton, Ontario, Canada
  • Krepinsky, Joan C., McMaster University, Hamilton, Ontario, Canada

Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America, characterized by glomerular accumulation of extracellular matrix (ECM) proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses plays a central role in its pathogenesis. We recently showed that the endoplasmic reticulum resident GRP78 translocates to the cell surface in response to HG, where it mediates Akt activation and downstream profibrotic responses in MC.
Transforming growth factor β1 (TGFβ1) is recognized as a central mediator of HG-induced profibrotic responses, but whether it is regulated by cell surface GRP78 (csGRP78) is unknown. TGFβ1 is stored in the ECM in a latent form, requiring release for biological activity. The matrix glycoprotein thrombospondin-1 (TSP-1) is an important factor in TGFβ1 activation, known to be increased in DKD and by HG in MC. Here we determined whether csGRP78 regulates the expression of TSP-1 and thereby TGFβ1 activation in HG.


Primary rat and mouse MC were treated with 30mM HG. TSP-1 upregulation and deposition into the ECM and TGFβ1 activation were assessed using standard molecular biology techniques.


TSP-1 transcript and promoter activity were increased by HG, as were cellular and ECM TSP-1, and these required PI3K/Akt activity. To determine whether csGRP78 was required, its activity was inhibited using vaspin or the C-terminal targeting antibody C38. Alternatively, GRP78 translocation to the cell surface was prevented with siRNA downregulation of its transport chaperone MTJ-1. All of these prevented HG-induced TSP-1 upregulation and deposition into the ECM. The HG-induced increase in active TGFβ1 in the medium was also inhibited, and this was associated with reduced intracellular Smad3 activation and signaling.


These data support an important role for csGRP78 in regulating HG-induced TSP-1 transcriptional induction via PI3K/Akt signaling. Functionally, this enables TGFβ1 activation in response to HG, with consequent increase in ECM proteins. Means of inhibiting csGRP78 signaling represent a novel target for preventing the DKD-associated fibrosis.
TGFβ1 is a central mediator of DKD, but its inhibition is not feasible due to adverse effects. Thus, indirect methods of attenuation are of current interest.


  • Government Support – Non-U.S.