Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis

Abstract

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 b (TGF-b) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-b/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.

Epithelial–mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis

“…The phenomenon that epithelial cells acquire mesenchymal traits, termed as epithelial–mesenchymal transition (EMT), has been observed in physiological and pathological processes, including embryogenesis (Gros & Tabin, ; Yoshino et al, ), inflammation (Correa‐Costa et al, ), fibrosis (Grande et al, ; Lovisa et al, ; Schneider et al, ), wound healing (Banerjee et al, ), and cancer progression (Ruscetti, Quach, Dadashian, Mulholland, & Wu, ; Wei et al, ). This morphology‐related plasticity is also a common theme in carcinogenesis where cancer‐initiating cells generate and invade.…”

STAT3 Targets ERR-α to Promote Epithelial–Mesenchymal Transition, Migration, and Invasion in Triple-Negative Breast Cancer Cells

“…One of the hallmarks of metastasis is that epithelial cells acquire mesenchymal traits, named EMT (30). Such a phenomenon has been found in many biological processes, like embryogenesis, inflammation, fibrosis, and wound healing (31)(32)(33)(34)(35)(36)(37). The EMT process is triggered by its specific activators, such as Slug, Snail, Twist, or ZEB1 (38)(39)(40).…”

Platelet-activating factor modulates fat storage in the liver induced by a high-refined carbohydrate-containing diet

“…This increase would be related with a higher deposition of collagen in the liver because PAF signaling appears to be important to trigger fibrogenesis [47,51,52]. Moreover, the use of a PAF antagonist decreases fibrosis in other tissues such as lung and subretinal tissues [53,54].…”