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

Abstract

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.

• Authors: Lan Yao, M Frances Wright, Brandon C Farmer, Laura S Peterson, Amir M Khan, Jianyong Zhong, Leslie Gewin, Chuan-Ming Hao, Hai-Chun Yang, Agnes B Fogo
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 34 Issue 12 Pg. 2042-2050 (12 01 2019) ISSN: 1460-2385 [Electronic] England
• PMID: 31071225 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chemical References

• Acta2 protein, mouse
• Actins
• CCN2 protein, mouse
• Collagen Type I
• Extracellular Matrix Proteins
• Nerve Tissue Proteins
• Serpin E2
• Serpine2 protein, mouse
• Transforming Growth Factor beta
• Connective Tissue Growth Factor
• neuronectin

Topics

• Actins (metabolism)
• Animals
• Collagen Type I (metabolism)
• Connective Tissue Growth Factor (metabolism)
• Extracellular Matrix Proteins (metabolism)
• Fibroblasts (metabolism)
• Fibrosis (etiology, metabolism, prevention & control)
• Kidney Diseases (etiology, metabolism, prevention & control)
• Mice
• Mice, Knockout
• Nerve Tissue Proteins (metabolism)
• Serpin E2 (physiology)
• Transforming Growth Factor beta (metabolism)
• Ureteral Obstruction (complications, metabolism)