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Updated: Mar 16, 2026
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Reduced expression of VAChT increases renal fibrosis
Reinaldo Correia Silva1, Fernanda Fernandes Terra1, Yuri Felipe Guise1
1Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
Insights
Reduced acetylcholine release exacerbates kidney fibrosis and inflammation in a mouse model of chronic kidney disease (CKD). Activating the α7 nicotinic acetylcholine receptor (α7 nAChR) pathway mitigated these damaging effects, suggesting a therapeutic target for kidney disease.
Area of Science:
- Nephrology
- Inflammation Research
- Neuroimmunology
Background:
- Chronic kidney disease (CKD) is a global health concern, often linked to diabetes and cardiovascular issues.
- Obstructive kidney disease is a primary cause of CKD in children.
- The cholinergic anti-inflammatory pathway, involving α7 nicotinic acetylcholine receptor (α7 nAChR) activation, can reduce inflammation and tissue damage.
Purpose of the Study:
- To investigate the role of endogenous acetylcholine in renal fibrosis development using a unilateral ureter obstruction (UUO) model.
- To assess the impact of reduced acetylcholine secretion on kidney inflammation and fibrogenesis.
Main Methods:
- Utilized genetically modified mice with reduced vesicular acetylcholine transporter (VAChT KD(hom) mice) to impair acetylcholine secretion.
- Induced kidney damage via unilateral ureter obstruction (UUO).
- Administered PNU-282987, a selective α7 nAChR agonist, to assess its protective effects.
Main Results:
- VAChT KD(hom) mice exhibited increased renal damage, proteinuria, and collagen deposition post-UUO compared to wild-type controls.
- Kidney inflammation, characterized by an enhanced TH1/TH17 response, was observed in VAChT mutant mice.
- PNU-282987 treatment significantly reduced kidney injury in VAChT KD(hom) mice following UUO.
Conclusions:
- Reduced acetylcholine release impairs the cholinergic anti-inflammatory pathway, promoting pro-inflammatory and pro-fibrotic responses in the kidney.
- Physiological activation of the cholinergic anti-inflammatory pathway plays a crucial role in regulating renal inflammatory responses.
- Targeting the cholinergic anti-inflammatory pathway presents a potential therapeutic strategy for kidney disease.
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.
