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Kidney Week

Abstract: TH-OR008

Novel Liposomal Nanocarriers of Preassembled Glycocalyx Restore Renal Microcirculation in Sepsis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Goligorsky, Michael S., New York Medical College, Valhalla, New York, United States
  • Sun, Dong, New York Medical College, Valhalla, New York, United States
Background

Endothelial cell dysfunction is a weighty contributor to the pathogenesis of sepsis. Endothelial glycocalyx (EG) is a guardian of endothelial functions, but during the course of sepsis its integrity is compromised. We observed that mice with the polymicrobial sepsis exhibit a drastic reduction in the global volume of EG. The loss of EG leads to leukocyte infiltration, impaired microvascular circulation, increased vascular permeability, thrombogenesis, and circulatory collapse, eventuating in the development of multiorgan dysfunction. Therapeutic attempts to prevent EG loss showed success, however, clinically more important restorative therapies of EG have been unsuccessful.

Methods

We have recently invented liposomal nanocarriers of preassembled EG (LNPEG) to expeditiously restore EG and halt vascular complications of sepsis. We used atomic force microscopy, DAF-based NO detection, flow-induced vasodilation and in vivo LPS Laser-Doppler studies.

Results

In vitro testing of LNPEG using atomic force microscopy of cultured endothelial cells showed that they increased thickness of EG and restored mechanoactivation-induced NO production, both severely affected by exposure to LPS. Ex vivo perfused isolated arterioles with degraded EG obtained from LPS-injected mice showed subnormal flow-induced dilation and exhibited increased vascular permeability, whereas perfusion of these vessels with LNPEG restored both and increased flow-induced NO production. In LPS mice, infusion of LNPEG either systemically or into the renal artery significantly improved renal microcirculation (laser-Doppler imaging and flowmetry). Electron microscopy of kidneys localized LNPEG to be tethered to or embedded into the plasma membrane of glomerular and peritubular capillary endothelial cells. Immunostaining of EG showed its significant restoration after administration of LNPEG.

Conclusion

In conclusion, this is the first demonstration that our invented LNPEG are functionally capable of expeditiously restoring EG and halting vascular complications of sepsis. In summary, wepropose that the early loss of EG facilitates multiorgan failure in sepsis, and treatment with LNPEG has a potential to alleviate it.