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Kidney Week

Abstract: TH-PO098

Protective Mechanisms of Lymphangiogenesis During Kidney Injury

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Donnan, Michael David, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Deb, Dilip K., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Lymphangiogenesis is demonstrated to be a protective response in multiple etiologies of kidney injury. As injury-related lymphangiogenesis is driven by the release of the growth factor VEGF-C by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the mechanisms by which kidney lymphangiogenesis protects the kidney against injury remain uncertain. Recent investigations in other organ systems have revealed lymphatic endothelial cells (LECs) secrete factors termed “lymphoangiocrine” molecules which directly promote protection against injury in surrounding tissues. Our hypothesis is that lymphangiocrine factors are also released by kidney LECs and convey protection against kidney injury.

Methods

We generated a conditional mouse model to promote lymphangiogenesis (VegfcGOF) through overexpressing VEGF-C in the kidney tubules using the Pax8-rtTA-TetOcre driver strain. The ischemia-reperfusion mouse model of acute kidney injury (IR-AKI) was performed on VegfcGOF mice and littermate controls and kidneys were collected 7 days post-injury. Kidneys were processed for standard histology, tissue clearing with 3D light-sheet imaging of the vasculature, and single-cell RNA sequencing.

Results

VegfcGOF mice demonstrate an expansion of lymphatic capillaries throughout the kidney cortex, which is further potentiated by IR-AKI. There is no baseline difference in BUN, creatinine, or blood pressure between VegfcGOF mice and littermate controls. At 7 days post-injury, kidneys demonstrate a similar level of peritubular capillary rarefaction, and expression of the injury marker Kim-1, however, VegfcGOF mice have a reduction in a distinct set of previously identified genes (Dcd2a, Sema5a, and Vcam1) that signify proximal tubule epithelial cells (PTECs) which have failed to repair after injury. Additionally, the known cardiac lymphangiocrine factor Reelin (RELN) is expressed by kidney LECs during injury with its receptor integrinß1 (ITGB1) expressed in tubule epithelial and stromal cells.

Conclusion

Kidney lymphangiogenesis is robustly induced in the VegfcGOF mice without overt consequence to kidney function at baseline. In the setting of kidney injury, kidney LECs may promote successful repair of PTECs with RELN-ITGB1 signaling being a potential mechanism of this protective effect.

Funding

  • NIDDK Support