Abstract: SA-PO717
Lymphatic Dysfunction and Perirenal Adiposity: Role of Glucocorticoids
Session Information
- Glomerular Diseases: Therapeutic Strategies
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Shelton, Elaine L., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Kon, Valentina, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Glucocorticoids (GCs) are commonly prescribed to treat proteinuric kidney injury, but their use often leads to negative side effects such as visceral adiposity. The impact of GCs on adipocyte growth is well-established, however, their effect on lipid clearance via lymphatic vessels is not understood. This study investigated GCs effects on lymphatic endothelial cell (LEC) permeability which underlies reabsorption of fluids, solutes and lipids from the interstitium and lymphatic vessel contractile functions which regulates transport of lipids.
Methods
Primary cultured mouse LECs were exposed to vehicle, dexamethasone (DXMS), or DXMS+glucocorticoid receptor (GR) antagonist (D06). RNA sequencing was performed and related genes were validated by rtPCR. Additionally, barrier integrity was analyzed by Transepithelial electrical resistance (TEER). Ex vivo pressure myography assessed the contractile function of renal lymphatic collecting vessels of rats treated with DXMS or vehicle x 2 weeks.
Results
GR was detected in both lymphatic vessels and cultured LECs. RNA sequencing revealed DXMS upregulated 771 genes and downregulated 693 genes, with DXMS+D06 reversing expression of 615 genes. GO enrichment and KEGG pathway analysis revealed changes in cell junction-related genes and rtPCR confirmed DXMS upregulation of TJP1 and Ocln junctional genes, reversed by D06. In TEER assays, DXMS increased barrier integrity of LECs. This effect could be reversed with addition of D06. Lymphatic vessels from DXMS-treated rats had reduced amplitude of contraction and ejection fraction. In vivo, DXMS increased perirenal fat by around 56% vs vehicle.
Conclusion
In conclusion, GCs expand perirenal adiposity and blunt lymphatic contractility together with increasing LECs tight junctions and reducing permeability through GR which we propose contribute to development of visceral adiposity.