Abstract: FR-PO968
Integrin-Linked Kinase Depletion Exerts Protective Effects in Vascular Fibrosis Associated With CKD
Session Information
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Campillo de Blas, Sofia, Department of Systems Biology, Physiology Unit, University of Alcala, Alcala de Henares, Madrid, Spain
- Gutierrez Calabres, Elena, Department of Systems Biology, Physiology Unit, University of Alcala, Alcala de Henares, Madrid, Spain
- de la Serna, Mariano, Biomedical Research Foundation, Hospital Universitario Principe de Asturias, Alcala de Henares, Madrid, Spain
- Canales Bueno, Natalia, NOVELREN, Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), Fundacion Renal Iñigo Alvarez de Toledo (FRIAT) and REDinREN, (ISCIII), Madrid, Madrid, Spain
- González Valero, Cristina, Department of Systems Biology, Physiology Unit, University of Alcala, Alcala de Henares, Madrid, Spain
- Griera, Mercedes, Department of Systems Biology, Physiology Unit, University of Alcala, Alcala de Henares, Madrid, Spain
- De frutos garcia, Sergio, Department of Systems Biology, Physiology Unit, University of Alcala, Biomedical Research Foundation, Hospital Universitario Principe de Asturias, Alcala de Henares, Madrid, Spain
- Rodriguez puyol, Diego, Nephrology Unit, Hospital Universitario Principe de Asturias, Biomedical Research Foundation, Hospital Universitario Principe de Asturias, Department of Systems Biology, Physiology Unit, University of Alcala, Alcala de Henares, Madrid, Spain
- Calleros, Laura, Department of Systems Biology, Physiology Unit, University of Alcala, Alcala de Henares, Madrid, Spain
Background
Cardiovascular diseases are one of the most common causes of morbidity and mortality in chronic kidney disease (CKD) patients. Integrin-linked kinase (ILK) is a serine/threonine protein kinase and a scaffold protein between the extracellular matrix and intracellular signaling pathways. The aim of this study was to investigate the role of ILK in CKD-associated vascular damage.
Methods
We induce CKD in both wild-type (WT) and adult conditional ILK knock-down (cKD-ILK) by feding mice with a 0.2% adenine-supplemented diet during 2, 4 or 6 weeks. Animals receiving this diet develop a tubulointerstitial damage resembling CKD observed in humans. Aortic tissue mRNA levels of ILK, fibrosis markers as the extracellular matrix proteins collagen type I, fibronectin and the profibrotic cytokine TGF-β1 were determined by RT-qPCR. By in vitro experiments in human aortic-vascular smooth muscle cells (HA-VSMC), we tested the effect of uremic toxins, indoxyl- and p-cresyl sulfate (IS and pCS), on ILK activity and ILK and fibrosis markers expression. We transfected the cells with ILK-specific siRNA to verified the effect of ILK-deletion in vascular fibrosis.
Results
We found a progressive and significant increase in the mRNA expression of ILK in adenine-fed WT mice that was not observed in cKD-ILK mice on the same diet. Moreover, a significant increase in mRNA levels of fibrosis markers and TGF-β1 in the adenine-fed WT mice was also observed, which was significantly lower in adenine-fed cKD-ILK mice. Interestingly, we found statistically significant correlations between the vascular mRNA content of ILK and the fibrosis markers and TGF-β1 (p < 0.0001, r between 0.81 and 0.82). In vitro experiments show an increase of ILK activity and fibrosis markers expression in the HA-VSMC treated with IS and pCS, while this increase was reversed in ILK-deleted cells.
Conclusion
ILK depletion protects against vascular fibrosis associated with CKD and TGF-β1 and consequent fibrosis increase is probably associated with an ILK-dependent mechanism. Therefore, ILK could be a potential therapeutic target for the prevention or treatment of development of vascular fibrosis in renal patients.
Funding
- Other NIH Support