PMID- 31071225 OWN - NLM STAT- MEDLINE DCOM- 20200430 LR - 20200430 IS - 1460-2385 (Electronic) IS - 0931-0509 (Print) IS - 0931-0509 (Linking) VI - 34 IP - 12 DP - 2019 Dec 1 TI - Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction. PG - 2042-2050 LID - 10.1093/ndt/gfz050 [doi] AB - 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 beta (TGF-beta) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF beta 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 (alpha-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. CI - (c) The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. FAU - Yao, Lan AU - Yao L AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Medical Healthcare Center, Beijing Friendship Hospital of Capital Medical University, Beijing, China. FAU - Wright, M Frances AU - Wright MF AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Farmer, Brandon C AU - Farmer BC AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Department of Biology, Western Kentucky University, Bowling Green, KY, USA. FAU - Peterson, Laura S AU - Peterson LS AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Khan, Amir M AU - Khan AM AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA. FAU - Zhong, Jianyong AU - Zhong J AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Gewin, Leslie AU - Gewin L AD - Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Hao, Chuan-Ming AU - Hao CM AD - Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China. FAU - Yang, Hai-Chun AU - Yang HC AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Fogo, Agnes B AU - Fogo AB AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA. AD - Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA. LA - eng GR - I01 BX003425/BX/BLRD VA/United States GR - R01 DK056942/DK/NIDDK NIH HHS/United States GR - R01 DK108968/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - England TA - Nephrol Dial Transplant JT - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JID - 8706402 RN - 0 (Acta2 protein, mouse) RN - 0 (Actins) RN - 0 (CCN2 protein, mouse) RN - 0 (Collagen Type I) RN - 0 (Extracellular Matrix Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Serpin E2) RN - 0 (Serpine2 protein, mouse) RN - 0 (Transforming Growth Factor beta) RN - 139568-91-5 (Connective Tissue Growth Factor) RN - AAU3ZC4196 (neuronectin) SB - IM MH - Actins/metabolism MH - Animals MH - Collagen Type I/metabolism MH - Connective Tissue Growth Factor/metabolism MH - Extracellular Matrix Proteins/metabolism MH - Fibroblasts/*metabolism MH - Fibrosis/etiology/metabolism/*prevention & control MH - Kidney Diseases/etiology/metabolism/*prevention & control MH - Mice MH - Mice, Knockout MH - Nerve Tissue Proteins/metabolism MH - Serpin E2/*physiology MH - Transforming Growth Factor beta/metabolism MH - Ureteral Obstruction/*complications/metabolism PMC - PMC6887698 OTO - NOTNLM OT - PAI-1 OT - fibroblast OT - interstitial fibrosis EDAT- 2019/05/10 06:00 MHDA- 2020/05/01 06:00 PMCR- 2020/04/10 CRDT- 2019/05/10 06:00 PHST- 2018/04/18 00:00 [received] PHST- 2019/02/20 00:00 [accepted] PHST- 2019/05/10 06:00 [pubmed] PHST- 2020/05/01 06:00 [medline] PHST- 2019/05/10 06:00 [entrez] PHST- 2020/04/10 00:00 [pmc-release] AID - 5443269 [pii] AID - gfz050 [pii] AID - 10.1093/ndt/gfz050 [doi] PST - ppublish SO - Nephrol Dial Transplant. 2019 Dec 1;34(12):2042-2050. doi: 10.1093/ndt/gfz050.