title: Reduced expression of VAChT increases renal fibrosis.
abstract: Chronic kidney disease (CKD) is associated with several other long-lasting conditions such as diabetes and cardiovascular diseases and it is a significant contributor to mortality worldwide. Obstructive kidney disease is one of the leading causes of CKD in children and may result from a wide variety of pathologic processes. Recent studies have shown that α7 nicotinic acetylcholine receptor (α7 nAChR) activation in the cholinergic anti-inflammatory pathway reduces production of inflammatory mediators and consequently prevents tissue injury and death. Here, we examined the role of endogenous release of acetylcholine on the development of fibrosis in renal tissue using a model of unilateral ureter obstruction (UUO)-induced CKD, in which obstruction promotes inflammation-mediated kidney damages. To interfere with acetylcholine secretion, we used mice in which the vesicular acetylcholine transporter is genetically reduced (VAChT KD(hom) mice). We observed a higher renal damage in VAChT mutant mice when compared to wild type controls, exemplified by higher proteinuria and increased amount of type 1 collagen in the kidney tissue, indicating accentuated fibrogenesis. These results were accompanied by enhanced localized kidney inflammation, with increased TH1/TH17 profile response. Administration of PNU-282987, a selective agonist of α7 nAChR, significantly attenuated kidney injury after UUO in VAChT KD(hom) mice, indicating that the lack of acetylcholine release decrease the action of the cholinergic anti-inflammatory pathway, promoting an up-regulation of pro-inflammatory and pro-fibrotic pathways. These results suggest that physiological activation of the cholinergic anti-inflammatory pathway regulates inflammatory responses in the kidney suggesting a new therapeutic approach for kidney disease.
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Reinaldo Correia
authors.initials: RC
authors.lastname: Silva
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Fernanda Fernandes
authors.initials: FF
authors.lastname: Terra
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Yuri Felipe
authors.initials: YF
authors.lastname: Guise
authors.affiliation: Robarts Research Institute, Department of Anatomy & Cell Biology and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Marco Antônio Máximo
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Robarts Research Institute, Department of Anatomy & Cell Biology and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Vânia Ferreira
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: Meire Ioshie
authors.initials: MI
authors.lastname: Hiyane
authors.affiliation: Department of Pathology, Faculty of Medicine, University of São Paulo, Brazil.
authors.forename: Denise Maria Avancini
authors.initials: DM
authors.lastname: Costa Malheiros
authors.affiliation: Department of Biosciences, Federal University of São Paulo (UNIFESP), Santos, Brazil.
authors.forename: Carla Maximo
authors.initials: CM
authors.lastname: Prado
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil; Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo (UNIFESP), São Paulo, Brazil; Renal Pathophysiology Laboratory (LIM16), Faculty of Medicine, University of São Paulo, Brazil.
authors.forename: Niels Olsen Saraiva
authors.initials: NO
authors.lastname: Camara
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil. Electronic address: tarcio.tb@gmail.com.
authors.forename: Tarcio Teodoro
authors.initials: TT
authors.lastname: Braga
keywords: Acetylcholine; Kidney fibrosis