Reduced expression of VAChT increases renal fibrosis

Reinaldo Correia Silva; Fernanda Fernandes Terra; Yuri Felipe Guise; Marco Antônio Máximo Prado; Vânia Ferreira Prado; Meire Ioshie Hiyane; Denise Maria Avancini Costa Malheiros; Carla Maximo Prado; Niels Olsen Saraiva Camara; Tarcio Teodoro Braga

doi:10.1016/j.pathophys.2016.07.002

Reduced expression of VAChT increases renal fibrosis

Pathophysiology. 2016 Sep;23(3):229-36. doi: 10.1016/j.pathophys.2016.07.002. Epub 2016 Aug 10.

Affiliations

¹ Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
² Robarts Research Institute, Department of Anatomy & Cell Biology and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
³ Department of Pathology, Faculty of Medicine, University of São Paulo, Brazil.
⁴ Department of Biosciences, Federal University of São Paulo (UNIFESP), Santos, Brazil.
⁵ 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.
⁶ 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.

PMID: 27524473
DOI: 10.1016/j.pathophys.2016.07.002

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.

Keywords: Acetylcholine; Kidney fibrosis.