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EMBO Mol Med. 2020 Jan 14:e11021. doi: 10.15252/emmm.201911021. [Epub ahead of print]

Dysregulated mesenchymal PDGFR-β drives kidney fibrosis.

Author information

1
Institute of Pathology, RWTH University of Aachen, Aachen, Germany.
2
Division of Nephrology, RWTH University of Aachen, Aachen, Germany.
3
Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany.
4
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5
Department of Nephrology, Monash Health, and Center for Inflammatory Diseases, Monash University, Melbourne, Vic., Australia.
6
Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Munich, Germany.
7
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
8
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
9
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University of Aachen, Aachen, Germany.
10
Interdisciplinary Center for Clinical Research (IZKF), RWTH University of Aachen, Aachen, Germany.
11
Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University, and Heidelberg University Hospital, Heidelberg, Germany.

Abstract

Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells. To study the consequences of PDGFR-β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR-β activation resembled those found in patients. In conclusion, PDGFR-β activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.

KEYWORDS:

PDGFR; anemia; chronic kidney disease; fibroblasts; progression

PMID:
31943786
DOI:
10.15252/emmm.201911021
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