Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis.
Platelet-activating factor (PAF) is a lipid mediator with important pro-inflammatory effects, being synthesized by several cell types including kidney cells. Although there is evidence of its involvement in acute renal dysfunction, its role in progressive kidney injury is not completely known. In the present study, we investigated the role of PAF receptor (PAFR) in an experimental model of chronic renal disease. Wild-type (WT) and PAFR knockout (KO) mice underwent unilateral ureter obstruction (UUO), and at kill time, urine and kidney tissue was collected. PAFR KO animals compared with WT mice present: (a) less renal dysfunction, evaluated by urine protein/creatinine ratio; (b) less fibrosis evaluated by collagen deposition, type I collagen, Lysyl Oxidase-1 (LOX-1) and transforming growth factor β (TGF-β) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-β/BMP-7 ratio); (c) downregulation of extracellular matrix (ECM) and adhesion molecule-related machinery genes; and (d) lower levels of pro-inflammatory cytokines. These indicate that PAFR engagement by PAF or PAF-like molecules generated during UUO potentiates renal dysfunction and fibrosis and might promote epithelial-to-mesenchymal transition (EMT). Also, early blockade of PAFR after UUO leads to a protective effect, with less fibrosis deposition. In conclusion, PAFR signaling contributes to a pro-inflammatory environment in the model of obstructive nephropathy, favoring the fibrotic process, which lately will generate renal dysfunction and progressive organ failure.
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Matheus
M
Correa-Costa
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Vinicius
V
Andrade-Oliveira
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Tarcio T
TT
Braga
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Angela
A
Castoldi
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Cristhiane F
CF
Aguiar
Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.
Clarice S T
CS
Origassa
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Andrea C D
AC
Rodas
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Meire I
MI
Hiyane
Pathology Department, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Denise M A C
DM
Malheiros
1] Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil [2] British Heart Foundation, Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Francisco J O
FJ
Rios
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Sonia
S
Jancar
1] Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil [2] Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.
Niels O S
NO
Câmara
D000818:Animals; D001381:Azepines; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009393:Nephritis / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D014230:Triazoles; D014517:Ureteral Obstruction
D001381:Azepines; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; D003094:Collagen; C063964:bepafant