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Abstract: SA-PO231

Loss of Glomerular Endothelial Surface Layer and Cell Integrity Is Mediated by Increased Ednra and Crosstalk with Podocyte Derived Edn1

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology


  • Ebefors, Kerstin, University of Gothenburg, Gothenburg, Sweden
  • Wiener, Robert, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Azeloglu, Evren U., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Haraldsson, Borje, University of Gothenburg, Gothenburg, Sweden
  • Daehn, Ilse S., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Chronic kidney disease is increasing in prevalence worldwide with the majority of cases caused by glomerular diseases, including diabetic and hypertensive nephropathy and glomerulonephritis. There is emerging evidence that the specialized fenestrated glomerular endothelial cells (ECs) maintain the charge selective barrier to proteinuria via the endothelial surface layer (ESL) or glycocalyx. The ESL is a polysaccharide gel that lines the luminal surface composed of glycosaminoglycans (GAGs). We have previously demonstrated that activated podocytes can release endothelin-1 (Edn1) causing stress and dysfunction of ECs via increased Edn receptor A (Ednra) and consequently, podocyte loss in mice. We hypothesize that podocyte-EC crosstalk results in loss of early glomerular endothelial integrity.


Ultrastructural assessment of glomerular ECs by scanning EM at different time points of Dox induced TGF-β type I receptor signaling specifically in podocytes (PodTbrI mice). We measured ESL thickness by intralipid infusion EM and IsolectinB4 (IB4). Atomic force microscopy (AFM) measured the nanomechanical properties of the ESL in murine glomerular ECs (mGEC), we measured IB4, heparan sulfate (HS) by FACS, Heparanase (Hpse) and Hyaluronidase (Hyal) expression by RT-PCR.


Compared to ECs of control mice showing extensive fenestration, we detected a striking loss of fenestrae and significant cellular blebbing after 4d of Dox in the absence of foot process effacement and significant microalbuminuria. After 4d of Dox, there was a robust reduction of ESL thickness, decreased further over time, and the ESL loss was prevented by Ednra inhibitor BQ-123. We examined whether loss of ESL is mediated by podocyte released Edn1. mGEC were treated with Edn1, or co-incubated with supernatant from Control (CtrlSN) or Dox (DoxSN) treated PodTbrI podocytes. AFM measurements showed a significant reduction in ESL by Edn1 and DoxSN, concomitant with decreased IB4 and HS, and prevented by BQ123. Upregulation of Hpse and Hyal expression denoted increased GAG degradation and remodeling by ECs in response to podocyte Edn1.


We show evidence of early crosstalk between podocytes and glomerular ECs that results in loss of EC integrity preceding podocyte foot process effacement in glomerular disease.


  • NIDDK Support