Abstract: TH-PO045
Sodium Channel Alpha Subunit Deletion in the Endothelium Reduces Renal Ischemia-Reperfusion Injury
Session Information
- AKI: Mechanisms - Primary Injury and Repair - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Barrera-Chimal, Jonatan, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
- Tarjus, Antoine, INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France
- González, Cecilia, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
- Amador-Martinez, Isabel, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
- Lopez-Marure, Rebeca, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
- Jaisser, Frederic, INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France
Background
The epithelial sodium channel (ENaC) has a well described role in epithelia, however its role in endothelial cells remains to be further characterized. It has been suggested that endothelial ENaC modulates endothelial cell stiffness and this in turns regulates nitric oxide (NO) synthesis through the endothelial nitric oxide synthase (eNOS). The physiological relevance of endothelial ENaC in pathological conditions where reduced NO bioavailability plays an essential role remains largely unexplored. Renal ischemia/reperfusion (IR) injury is characterized by vasoconstriction, sustained decrease in renal perfusion and reduced oxygen supply causing tubular and endothelial cell injury. The decline of kidney blood flow is partly explained by a reduction in NO bioavailability. ENaC regulation of eNOS activity might have an influence in ischemic AKI.
We aimed to explore if endothelial ENaC deficiency has an impact on the severity of renal injury induced by IR.
Methods
Male mice with specific alpha ENaC subunit gene inactivation in the endothelium (endo-αENaCKO, n=26) and control littermates (n=26) were subjected to bilateral renal ischemia of 22 min or sham surgery. Kidney tissue hypoxia was evaluated at 3 hours by pimonidazole staining in 5 mice of each group. After 24 hours of reperfusion, kidney function and tubular injury was evaluated. Human endothelial cells (HMEC-1) in culture were used to study eNOS activation state under ENaC inhibition with amiloride 1mM for 24 hours, as compared to control cells.
Results
In control littermates, renal ischemia induced an increase in plasma creatinine (2-fold) and urea (1.7-fold), augmented Kim-1(100-fold) and NGAL (40-fold) mRNA levels and produced severe tubular injury as quantified by the tubular injury score. The absence of endothelial alpha ENaC subunit ameliorated renal tubular injury (p<0.05) and renal dysfunction (p<0.001). Moreover, endo-αENaCKO mice recovered faster from renal hypoxia after the ischemia episode as compared to littermates as shown by reduced pimonidazole staining. In HMEC-1 cells, pharmacological ENaC inhibition promoted eNOS coupling and activation.
Conclusion
Our data suggest an important role for endothelial αENaC in renal IR, through improving eNOS activation and kidney perfusion.
Funding
- Government Support - Non-U.S.