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Kidney Week

Abstract: FR-OR022

Genetically Augmenting Renal Lymphangiogenesis Protects Against Inflammation Following AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Baranwal, Gaurav, Texas A&M College of Medicine, College Station, Texas, United States
  • Rutkowski, Joseph M., Texas A&M College of Medicine, College Station, Texas, United States
Background

Acute kidney injury (AKI) is a major cause of patient mortality and experimental data suggest AKI as an increased risk factor for progression to chronic kidney disease (CKD). The pathological transition from AKI to CKD is not well understood. Not only the degree of the initial AKI inflammatory response, but also how well it resolves - both in time and in function - are likely factors dictating the potential for future CKD progression. Lymphatic vessels and lymphangiogenesis (LAG) are necessary to maintain tissue homeostasis through fluid, macromolecule, and immune cell clearance. Inflammation-associated LAG is necessary for a timely resolution of peripheral inflammation. What roles renal lymphatics play in AKI recovery or CKD progression is largely unknown.

Methods

We have recently characterized transgenic mice that overexpress the potently lymphangiogenic signal VEGF-D only in the kidney upon doxycycline administration. These conditional “KidVD” mice exhibit marked lymphangiogenesis throughout the kidney. To test if a kidney-specific increase in lymphatic density was protective in AKI, we utilized KidVD mice in the well-characterized surgical bilateral ischemia reperfusion (I/R) model. We also crossed KidVD mice to the POD-ATTAC mouse line, a model of inducible podocyte apoptosis and proteinuria.

Results

First, we identified an endogenous upregulation of lymphatic growth factors VEGF-C and VEGF-D with a small degree of inflammation-associated LAG in both models absent genetic LAG induction. Second, when renal LAG was first induced on the KidVD background prior to injury, we found reduced expression of inflammatory cytokines and matrix fibrosis at 7 days post insult in both models. POD-ATTAC x KidVD mice demonstrated reduced interstitial fibrosis and reduced immune cell numbers 28 days following podocyte loss. Interestingly, despite improvements in inflammation, serum creatinine and eGFR were not improved in KidVD mice in either AKI model and KidVD mice demonstrated increased sodium excretion.

Conclusion

These data suggest that specifically increasing renal LAG signaling may reduce inflammation and fibrosis, but may concurrently disturb transport homeostasis. Renal lymphatic density in response to AKI may thus be predictive in identifying and targeting inflammatory CKD progression.