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

Title
Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy
Authors
Jo, Hyung AhHyeon, Jin SeongYang, Seung HeeJung, YoungaeHa, HunjooJeong, Chang WookKwak, CheolKim, YaerimLee, HajeongLee, Jung PyoJoo, Kwon WookLim, Chun SooKim, Yon SuHwang, Geum-SookKim, Dong Ki
Ewha Authors
하헌주황금숙
SCOPUS Author ID
하헌주scopus; 황금숙scopus
Issue Date
2021
Journal Title
KIDNEY INTERNATIONAL
ISSN
0085-2538JCR Link

1523-1755JCR Link
Citation
KIDNEY INTERNATIONAL vol. 99, no. 2, pp. 443 - 455
Keywords
fumaratemetabolomicsPLA2R-associated membranous nephropathy
Publisher
ELSEVIER SCIENCE INC
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
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.
DOI
10.1016/j.kint.2020.06.031
Appears in Collections:
약학대학 > 약학과 > Journal papers
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