Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction.

Yao L, Wright MF, Farmer BC, Peterson LS, Khan AM, Zhong J, Gewin L, Hao CM, Yang HC, Fogo AB
Nephrol Dial Transplant. 2019 34 (12): 2042-2050

PMID: 31071225 · PMCID: PMC6887698 · DOI:10.1093/ndt/gfz050

BACKGROUND - Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1).

METHODS - Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later.

RESULTS - GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice.

CONCLUSION - These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.

© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

MeSH Terms (14)

Actins Animals Collagen Type I Connective Tissue Growth Factor Extracellular Matrix Proteins Fibroblasts Fibrosis Kidney Diseases Mice Mice, Knockout Nerve Tissue Proteins Serpin E2 Transforming Growth Factor beta Ureteral Obstruction

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