膜性肾病
足细胞
富马酸二甲酯
内科学
内分泌学
自身免疫
延胡索酶
化学
医学
肾
肾小球肾炎
生物
免疫学
抗体
蛋白尿
生物化学
酶
多发性硬化
作者
Hyung Ah Jo,Jin Seong Hyeon,Seung Hee Yang,Youngae Jung,Hunjoo Ha,Chang Wook Jeong,Cheol Kwak,Yaerim Kim,Hajeong Lee,Jung Pyo Lee,Kwon Wook Joo,Chun Soo Lim,Yon Su Kim,Geum‐Sook Hwang,Yon Su Kim
标识
DOI:10.1016/j.kint.2020.06.031
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI