Abstract: SA-PO300
The Role of Plekha7 in Renal Fibrosis
Session Information
- Extracellular Matrix Biology, Fibrosis, Cell Adhesion
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Cell Biology
- 204 Extracellular Matrix Biology, Fibrosis, Cell Adhesion
Authors
- Yeboah, Michael M., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Chesnik, Marla A., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background
Chronic kidney disease (CKD) affects about 12% of all adults in the United States and is associated with significant morbidity, including but not limited to progression to end-stage kidney failure, and increased cardiovascular death. The associated healthcare costs are enormous and continues to increase. Progressive tubule-interstitial fibrosis (TIF) is the hallmark of CKD irrespective of the underlying kidney disease. TIF results from excessive deposition and accumulation of extracellular matrix in the renal interstitium by myofibroblasts which may originate from tubular epithelial cells through a process called epithelial-mesenchymal transition (EMT). The pleckstrin homology domain containing family A member 7 (Plekha7) is a novel protein that is localized at the adherens junction of epithelial cells in association with E-cadherin which is involved with intercellular contacts. Plekha7 is also linked to signaling molecules (including β-catenin) and the cellular cytoskeleton. A SNP in Plekha7 has been associated with hypertension in multiple genome-wide association studies, and mutation of Plekha7 in rats leads to a reduction in salt-sensitive hypertension. In this study, we examined a possible role of Plekha7 in modulating EMT and development of renal fibrosis .
Methods
In vivo, plekha7 mutant and wild type rats underwent unilateral ureteral obstruction (UUO), an established model of kidney fibrosis. The animals were euthanized after 2 weeks and the kidneys were retrieved for analysis of fibrosis markers. In vitro, plekha7 was stably knocked down or overexpressed in HK-2 cells via lentiviral transduction.
Results
Plekha7 mutation resulted in increased TGF-beta expression, macrophage recruitment, and fibrosis in rat kidneys after UUO. In HK-2 cells, plekha7 knockdown reduced E-cadherin and increased alpha-smooth muscle actin and collagen 1A1 expression, while plekha7 overexpression in the cells was associated with increased E-cadherin and reduced fibronectin and collagen 1A1 expression.
Conclusion
Mutation of Plekha7 results in increased renal fibrosis in rats. Knockdown of plekha7 promotes EMT in HK-2 cells, while plekha7 overexpression restores the epithelial phenotype and reduces TGF-β-induced EMT.
Funding
- Clinical Revenue Support