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Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy

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Author(s)
Hyung Ah Jo Jin Seong HyeonSeung Hee Yang Youngae Jung Hunjoo Ha Chang Wook Jeong Cheol Kwak Yaerim Kim Hajeong Lee Jung Pyo Lee Kwon Wook Joo Chun Soo LimYon Su Kim Geum-Sook Hwang Dong Ki Kim 
Keimyung Author(s)
Kim, Yae Rim
Department
Dept. of Internal Medicine (내과학)
Journal Title
Kidney international
Issued Date
2020
Volume
99
Issue
2
Keyword
fumaratemetabolomicsPLA2R-associated membranous nephropathy
Abstract
Downstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. healthy controls and vs. MCD: 1.76 and 1.60, respectively]. High urinary fumarate levels could predict the composite outcome of PLA2R-associated MN. Fumarate hydratase, which hydrolyzes fumarate, colocalized with podocalyxin, and its expression was lower in glomerular sections from patients with PLA2R-associated MN than in those from healthy individuals, patients with non-PLA2R-associated MN or MCD. Podocytes stimulated with IgG purified from serum with a high anti-PLA2R titer (MN-IgG) decreased expression of fumarate hydratase and increased fumarate levels. These changes were coupled to alterations in the expression of molecules involved in the phenotypic profile of podocytes (WT1, ZO-1, Snail, and fibronectin), an increase in albumin flux across the podocyte layer and the production of reactive oxygen species in podocytes. However, overexpression of fumarate hydratase ameliorated these alterations. Furthermore, knockdown of fumarate hydratase exhibited synergistic effects with MN-IgG treatment. Thus, fumarate may promote changes in the phenotypic profiles of podocytes after the development of PLA2R autoimmunity. These findings suggest that fumarate could serve as a potential target for the treatment of PLA2R-associated MN.
Keimyung Author(s)(Kor)
김예림
Publisher
School of Medicine (의과대학)
Citation
Hyung Ah Jo et al. (2020). Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy. Kidney international, 99(2), 443–455. doi: 10.1016/j.kint.2020.06.031
Type
Article
ISSN
0085-2538
Source
https://www.sciencedirect.com/science/article/pii/S0085253820308255
DOI
10.1016/j.kint.2020.06.031
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/43211
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
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