Abstract: SA-PO235
Endothelial Epas1 Deficiency Is Sufficient to Promote PEC Activation and FSGS in Experimental Hypertension
Session Information
- Glomerular: Cell Biology
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Glomerular
- 1003 Glomerular: Cell Biology
Authors
- Lenoir, Olivia, INSERM, Paris, France
- Luque, Yosu, INSERM U702, PARIS, France
- Baudrie, Veronique, inserm U970, Paris, France
- Sandrine, Placier, INSERM U702, PARIS, France
- Mesnard, Laurent, INSERM U702, PARIS, France
- Rondeau, Eric, APHP; University Paris 6, PARIS, France
- Tharaux, Pierre-Louis, INSERM, Paris, France
Background
Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. It is still a complex, only partially understood disease. Progressive sclerosis represents a hallmark of focal segmental glomerulosclerosis. Genetic tracing studies showed that parietal epithelial cells participate in the formation of sclerotic lesions. The loss of podocytes triggers a focal activation of parietal epithelial cells, which subsequently form cellular adhesions with the capillary tuft. Meanwhile, in the absence of intrinsic podocyte alteration, the origin of the pathogenic signal that could trigger parietal epithelial cells recruitment is elusive.
We studied the role of the endothelial PAS domain protein 1, a regulatory α subunit of the Hypoxia Inducible Factor complex, during angiotensin II-induced hypertensive nephropathy. Here, we hypothesized that endothelial EPAS1 could drive protection against Ang II-induced hypertension and glomerular injury leading to CKD.
Methods
To understand the role of endothelial EPAS1 during hypertensive nephropathy, we used a genetic approach to abrogate EPAS1 from endothelial cells in Ang II-induced hypertension in mice.
Results
We found that endothelial EPAS1 protects from glomerular injury induced by chronic hypertension. We also observed that endothelial EPAS1 abrogation aggravates podocyte and parietal epithelial cell (PEC) injury in a blood pressure-independent manner and impairs renal local vasoreactivity to Ang II.
Conclusion
The murine Ang II-induced hypertension developed in this study revealed a protective role of endothelial EPAS1 maintaining glomerular integrity during the hypertensive chronic insult. Interestingly, endothelial Epas1 gene deficiency promoted podocyte damage and parietal epithelial cells activation and segmental sclerosis, supporting proof of principle that endothelial-derived signal can trigger FSGS. This also suggests that endothelial EPAS1 dysfunction could be a susceptibility factor for hypertension-associated FSGS lesions and CKD progression with endothelial Epas1 functional variants or interacting pathways being potential key modifiers to understand secondary FSGS-lesions.
Funding
- Government Support - Non-U.S.