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Kidney Week

Abstract: TH-PO768

Cyclosporine Induces Fenestral Injury in Bioengineered Human Kidney Microvessels

Session Information

  • Bioengineering
    October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bioengineering

  • 300 Bioengineering


  • Nagao, Ryan J., University of Washington, Seattle, Washington, United States
  • Akilesh, Shreeram, University of Washington, Seattle, Washington, United States
  • Pippin, Jeffrey W., University of Washington, Seattle, Washington, United States
  • Kelly, Edward J., University of Washington, Seattle, Washington, United States
  • Shankland, Stuart J., University of Washington, Seattle, Washington, United States
  • Himmelfarb, Jonathan, Kidney Research Institute, Seattle, Washington, United States
  • Zheng, Ying, University of Washington, Seattle, Washington, United States

The use of cyclosporine A (CsA), a potent calcineurin inhibitor and immunosuppressant drug, has greatly improved the survival of patients receiving organ transplants, but also frequently results in significant nephrotoxicity. Transplant patients treated with CsA have developed acute kidney injury with arteriolopathy, thrombotic microangiopathy (TMA) and tubulopathy. However, the mechanisms underlying human kidney-specific toxicological sensitivity to CsA are still poorly understood. Thus, there is a need to build human
kidney-specific biomimetic models capable of replicating clinical patterns of CsA-induced kidney injury.


Here, using 2-D culture and bioengineered 3-D microvessels containing human kidney peritubular microvascular endothelial cells (HKMECs), we show CsA exposure at as little as 1 h at 1 μg/mL leads to endothelial injury not observed using human umbilical vein microvascular endothelial cells (HUVECs). We then analyzed clinical biopsies of patients who recieived CsA and expressed TMA for the presence of peritubular capillary dysfunction.


CsA induced dysfunction in HKMECs characterized by the loss of fenestrae, shear stress-related changes in cell morphology, signs of vascular inflammation, erythrocyte adhesion to the luminal surface of the endothelium and extravasation of erythrocytes into the interstitial space, whereas HUVECs were unaffected. CsA disrupted the formation of the fenestral diaphragm protein, PV-1. Vascular endothelial growth factor (VEGF) signaling, which is known to be integral to support fenestrae, was also blocked by CsA, whereas adding VEGF partially protected HKMECs from CsA-induced morphologic changes. Integrated genome regulatory analyses identified key distinctions in the landscapes of HKMECs compared to HUVECs, particularly around genes related to formation and maintenance of fenestrae. Kidney transplant biopsies from patients experiencing CsA toxicity showed a loss of PV-1 and evidence of erythrocyte extravasation which are consistent with changes in our bioengineered kidney 3-D microvessels.


These data demonstrate that CsA directly targets human kidney microvascular endothelial cells, disrupting their fenestral structure and function, and provides novel insights into kidney-specific organotypic mechanisms of CsA-induced microvascular injury.


  • NIDDK Support