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Abstract: SA-PO308

Impaired Lymphatic Vessel Function Contributes to Edema in Nephrotic Syndrome

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Shelton, Elaine L., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kon, Valentina, Vanderbilt University, Nashville, Tennessee, United States
Background

Edema is a cardinal feature of nephrotic syndrome (NS) although the underlying mechanisms are incompletely understood. Lymphatic vessels transfer fluids, solutes, and macromolecules from the interstitial space back into the circulation. We examined the structure and function of lymphatics in the puromycin aminonucleoside (PAN) model of NS.

Methods

PAN was induced in Sprague Dawley rats, while non-injected rats served as controls (Cont). Eight days later, blood, urine, renal and mesenteric lymph, kidney and ileum were analyzed. Renal lymphatic vessels were isolated, cannulated and mounted in a perfusion chamber to assess vasoactivity.

Results

PAN caused the expected proteinuria, hypoalbuminemia, hyperlipidemia and generalized edema including in the kidney and ileum. Compared to Cont, PAN increased lymphangiogenesis, reflected by significantly increased gene expression of podoplanin (1.7-fold), VEGFR3 (2.1-fold) and the number of lymphatic vessels. VEGF-C, the major growth factor for lymphangiogenesis was elevated (2.1-fold) and lymph contained significantly more VEGF-A (2.0-3.1-fold) in PAN vs Cont. Lymphatic endothelial cells (LEC) isolated from mesenteric collecting vessel showed significantly increased gene expression of VE-cadherin (2.2-fold) while ileal LECs had increased ZO-1 (2.7-fold) indicating intercellular junction transition from button to zipper type. Isolated renal collecting lymphatic vessels from PAN showed significantly increased vessel diameter (15%), deceased contraction frequency (30%), and reduced sensitivity to endothelial NO inhibitor (L-NAME), NO donor (sodium nitroprusside), and thromboxane A agonist (U46619).

Conclusion

Although edema-forming kidney injury increases the number of lymphatic vessels, this compensation is inadequate, and edema rather reflects impaired vessel function, e.g., reduced lymphatic vessel contractility and reabsorptive capacity that may be novel targets in edema-forming disorders.

Funding

  • NIDDK Support