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postgraduate thesis: The role of acetate in the pathogenesis of lupus nephritis
Title | The role of acetate in the pathogenesis of lupus nephritis |
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Authors | |
Advisors | |
Issue Date | 2022 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Wong, N. L. E. [黃雅欒]. (2022). The role of acetate in the pathogenesis of lupus nephritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Lupus nephritis is a common cause of acute kidney injury that can lead to chronic kidney failure. Pathogenesis of lupus nephritis is complex and involves both genetic and environmental factors. Emerging evidence suggests that the gut microbiota and their metabolites play important roles in autoimmune diseases. Short chain fatty acids (SCFA) are metabolites generated in the colon by bacterial fermentation of dietary fibre and resistant starch. Acetate is the predominant SCFA produced and it is absorbed into the bloodstream then distributed to biological fluids and tissues distant to the gastrointestinal tract at varying concentrations. Acetate can exert variable effects on immune and non-immune cells pertinent to inflammation and fibrogenesis depending on its concentration and the cell type, through binding to its receptors, namely G protein-coupled receptor-41 (GPR41) and GPR43. The role of acetate in the pathogenesis of lupus nephritis has not been explored.
In this project, we investigated the effect of acetate on clinical, serological and histological parameters of disease in NZB/W F1 mice, an established murine model of lupus nephritis, focusing on inflammatory and fibrotic processes. Eight week old female NZB/W F1 mice were randomised to receive drinking water alone or with sodium acetate (200 mM) for 30 weeks, after which time blood was collected and kidney and colon specimens harvested. Age- and sex-matched BALB/c mice served as controls. The results showed that serum acetate level was significantly reduced in NZB/W F1 mice which manifested active nephritis compared with controls. Kidney histology in untreated NZB/W F1 mice showed mesangial expansion, immune cell infiltration, progressive glomerulosclerosis, tubular atrophy and interstitial fibrosis. Also, active nephritis was accompanied by increased gut permeability measured with dextran-FITC. GPR43, but not GPR41, was expressed in the colon of NZB/W F1 mice with active nephritis. Acetate treatment delayed proteinuria by approximately 3 weeks compared to untreated NZB/W F1 mice, and significantly improved kidney function and histology; but did not affect serum anti-dsDNA antibody level.
Kidney specimens from NZB/W F1 mice with active nephritis showed increased GPR41 and GPR43 expression compared with BALB/c mice, both predominantly localised to proximal renal tubular epithelial cells. In vitro studies with cultured HK-2 cells showed that over-expression of GPR41 or GPR43 had no effect on cell proliferation, but decreased IL-10 secretion, and increased TNF-α, IL-6, IL-8 and fibronectin expression under basal conditions. Upon incubation with acetate, TNF-α, IL-6, IL-8 and fibronectin expression was further augmented. Increased fibronectin expression was mediated in part through p38-MAPK and PI3K phosphorylation.
In summary, our data demonstrated that, while acetate showed a possible beneficial effect on kidney histology and function in lupus nephritis of NZB/W F1 mice, over-expression of GPR41 and GPR43 in proximal tubular epithelial cells may enhance inflammatory and fibrotic responses. The differential concentrations of acetate in different organs may be important in determining its impact on disease progression. |
Degree | Master of Philosophy |
Subject | Acetates lupus nephritis - Pathogenesis |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/328200 |
DC Field | Value | Language |
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dc.contributor.advisor | Yung, SSY | - |
dc.contributor.advisor | Chan, DTM | - |
dc.contributor.author | Wong, Nga Luen Ellen | - |
dc.contributor.author | 黃雅欒 | - |
dc.date.accessioned | 2023-06-05T09:05:57Z | - |
dc.date.available | 2023-06-05T09:05:57Z | - |
dc.date.issued | 2022 | - |
dc.identifier.citation | Wong, N. L. E. [黃雅欒]. (2022). The role of acetate in the pathogenesis of lupus nephritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/328200 | - |
dc.description.abstract | Lupus nephritis is a common cause of acute kidney injury that can lead to chronic kidney failure. Pathogenesis of lupus nephritis is complex and involves both genetic and environmental factors. Emerging evidence suggests that the gut microbiota and their metabolites play important roles in autoimmune diseases. Short chain fatty acids (SCFA) are metabolites generated in the colon by bacterial fermentation of dietary fibre and resistant starch. Acetate is the predominant SCFA produced and it is absorbed into the bloodstream then distributed to biological fluids and tissues distant to the gastrointestinal tract at varying concentrations. Acetate can exert variable effects on immune and non-immune cells pertinent to inflammation and fibrogenesis depending on its concentration and the cell type, through binding to its receptors, namely G protein-coupled receptor-41 (GPR41) and GPR43. The role of acetate in the pathogenesis of lupus nephritis has not been explored. In this project, we investigated the effect of acetate on clinical, serological and histological parameters of disease in NZB/W F1 mice, an established murine model of lupus nephritis, focusing on inflammatory and fibrotic processes. Eight week old female NZB/W F1 mice were randomised to receive drinking water alone or with sodium acetate (200 mM) for 30 weeks, after which time blood was collected and kidney and colon specimens harvested. Age- and sex-matched BALB/c mice served as controls. The results showed that serum acetate level was significantly reduced in NZB/W F1 mice which manifested active nephritis compared with controls. Kidney histology in untreated NZB/W F1 mice showed mesangial expansion, immune cell infiltration, progressive glomerulosclerosis, tubular atrophy and interstitial fibrosis. Also, active nephritis was accompanied by increased gut permeability measured with dextran-FITC. GPR43, but not GPR41, was expressed in the colon of NZB/W F1 mice with active nephritis. Acetate treatment delayed proteinuria by approximately 3 weeks compared to untreated NZB/W F1 mice, and significantly improved kidney function and histology; but did not affect serum anti-dsDNA antibody level. Kidney specimens from NZB/W F1 mice with active nephritis showed increased GPR41 and GPR43 expression compared with BALB/c mice, both predominantly localised to proximal renal tubular epithelial cells. In vitro studies with cultured HK-2 cells showed that over-expression of GPR41 or GPR43 had no effect on cell proliferation, but decreased IL-10 secretion, and increased TNF-α, IL-6, IL-8 and fibronectin expression under basal conditions. Upon incubation with acetate, TNF-α, IL-6, IL-8 and fibronectin expression was further augmented. Increased fibronectin expression was mediated in part through p38-MAPK and PI3K phosphorylation. In summary, our data demonstrated that, while acetate showed a possible beneficial effect on kidney histology and function in lupus nephritis of NZB/W F1 mice, over-expression of GPR41 and GPR43 in proximal tubular epithelial cells may enhance inflammatory and fibrotic responses. The differential concentrations of acetate in different organs may be important in determining its impact on disease progression. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Acetates | - |
dc.subject.lcsh | lupus nephritis - Pathogenesis | - |
dc.title | The role of acetate in the pathogenesis of lupus nephritis | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Master of Philosophy | - |
dc.description.thesislevel | Master | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2022 | - |
dc.identifier.mmsid | 991044550303503414 | - |