Kidney Week

Abstract: TH-PO942

Glucocorticoid Treatment Induces Lymphatic Dysfunction via ATP-Sensitive Potassium Channel

Session Information

• Health Maintenance, Nutrition, Metabolism - I
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Health Maintenance, Nutrition, and Metabolism

• 1500 Health Maintenance, Nutrition, and Metabolism

Authors

• Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jianyong Zhong,

• Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Haichun Yang,

• Shelton, Elaine L., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Elaine L. Shelton,

• Kon, Valentina, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Valentina Kon,

Background

Previously, we showed proteinuric disease impairs lymphatic vessel function. Glucocorticoid (GC) therapy is a cornerstone treatment of proteinuric diseases but commonly increases adiposity. Since lymphatics are the principal conduit for transport of lipoprotein particles and clearance of excess lipids, adiposity has been proposed as an indicator of impaired lymphatic function. We investigated whether glucocorticoids directly disrupt lymphatic integrity and function.

Methods

We exposed cultured lymphatic endothelial cells (LECs) to dexamethasone (DXMS) or control medium and assessed relevant parameters including proliferation, migration, and expression of tight junction protein-1 (TJP1), vascular endothelial growth factor receptor 3 (VEGFR3 or flt4), and caspase 2/3/9 (caps2/3/9) genes. Ex vivo myography studies evaluated DXMS effects on dynamics by exposing isolated rat mesenteric lymphatic vessels to increasing concentrations of DXMS. We also studied mesenteric lymphatic dynamics in vessels harvested from rats receiving daily DXMS or vehicle x 2 weeks. Finally, we evaluated effects of chronic DXMS exposure on response to vasoactive agents: L-NAME, PGE₂, furosemide, and pinacidil, an ATP-sensitive potassium channel (K_ATP) agonist.

Results

Our findings revealed that DXMS significantly reduces proliferation, migration, and TJP1 gene expression in LECs, while enhancing Flt4 gene expression. DXMS did not alter apoptosis of LECs. In mesenteric lymphatic vessels isolated from normal rats, DXMS increased frequency and end-systolic diameter (ESD), along with decreased amplitude of contraction (AMP) and ejection fraction (EF) with little effects on end-diastolic diameter (EDD). Similarly, vessels from DXSM-treated rats had decreased AMP and EF vs vehicle-treated rats. Moreover, chronic exposure to DXMS dramatically diminished responsiveness to pinacidil when compared to vessels of control rats, suggesting that DXMS can alter lymphatic function via modulation of K_ATP channels.

Conclusion

Our data suggest the novel observations that glucocorticoids are powerful modulators of lymphatic vessel function, lymphatic endothelial cell integrity and growth. These alterations may contribute to impaired lipid clearance and visceral adiposity commonly associated with glucocorticoid therapy in the context of proteinuric kidney disease.

Funding

• Other NIH Support