Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis

Abstract

Kidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in renal epithelial cells and demonstrate its decrease in renal tubules of murine and human fibrotic kidneys, as well as its downregulation in renal proximal tubular epithelial cells (RPTECs) after TGF-β1 treatment. shRNA-mediated knockdown of SNCA in RPTECs results in de novo expression of vimentin and α-SMA, while SNCA overexpression represses TGF-β1-induced mesenchymal markers. Conditional gene silencing of SNCA in RPTECs leads to an exacerbated tubulointerstitial fibrosis (TIF) in two unrelated in vivo fibrotic models, which is associated with an increased activation of MAPK-p38 and PI3K-Akt pathways. Our study provides an evidence that disruption of SNCA signaling in RPTECs contributes to the pathogenesis of renal TIF by facilitating partial epithelial-to-mesenchymal transition and extracellular matrix accumulation.

This work was supported by research grants PI15/00960 and PI17/00119 from the Instituto de Salud Carlos III (ISCII, Spanish Ministry of Economy and Competitiveness) and REDinREN (RD12/0021). The work on human kidney tissue samples was supported by the IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS PT17/0015/0027. M.B. was supported by the REDinREN (RD12/0021/0026) and Department of Health, Government of Catalonia (PERIS 2016-2020, SLT002/16/00178). M.C. was supported by the studentship from the Catalan Government (AGAUR). R.R.R-D. was supported by a grant from the Comunidad Autonóma de Madrid (B2017/BMD-3751 NOVELREN-CM). We thank Dr. Bernard Schneider (Swiss Federal Institute of Technology Lausanne, Switzerland) for providing pSIN-pgk-human Synuclein WT-WPRE plasmid, Dr. Guadalupe Sabio (CNIC, Madrid, Spain) for providing HA-p38 PCNA plasmid, and Dr. Volker Haase (Vanderbilt University, TN, USA) for providing PEPCK-Cre+ transgenic mice. We thank Laura Santos-Sanchez (Universidad Autonoma Madrid) for helping with collagen evaluation and immunohistochemistry studies, and Alicia Garcia (IRBLleida) for valuable technical help in the laboratory.