Abstract
To investigate whether the human anti-thrombospondin type 1 domain-containing 7A (THSD7A) antibody-induced membranous nephropathy (MN) is mediated by activating lectin complement pathway. Automatic biochemical apparatus was used to assess renal function of mice. The serum levels of anti-THSD7A antibodies and complement were tested by using ELISA. The expression level of THSD7A and mannose-binding lectin (MBL) in clinical tissue, and the histological features of MN in mice were examined by immunochemical methods. We found that THSD7A, MBL, and complement expression level from patients with circulating anti-THSD7A antibodies were significantly higher than that in normal group. Furthermore, difference of renal function in anti-THSD7A antibody-containing serum treatment groups and control groups was significant. Meanwhile, human anti-THSD7A autoantibodies activated the complement system and induced the histological features of MN in mice. In conclusion, human anti-THSD7A antibodies induce MN through activating MBL lectin complement pathway in mice.
Highlights
Membranous nephropathy (MN) is a common cause of nephrotic syndrome
The results showed that staining of thrombospondin type domain-containing 7A (THSD7A) and mannose-binding lectin (MBL) was notably stronger in the idiopathic MN (IMN) group than than in the normal group. (Figure 1A,B)
The research indicates that human MN is associated with the discoveries of neutral endopeptidase (NEP) PLA2R1 and THSD7A [20,21,22]
Summary
Membranous nephropathy (MN) is a common cause of nephrotic syndrome. It is characterized by the presence of immune complex deposits along with the glomerular basement membrane (GBM), resulting in thickening of the GBM and podocyte foot process effacement [1]. M-type phospholipase A2 receptor (M-PLA2R), a subtype of IgG4, was identified as a specific pathogenic target antigen in most patients with IMN [11]. It has been reported that expression of MBL-associated serine protease-1 (MASP-1), MASP-2, and MBL is a significantly elevated in the patients with positive PLA2R antibodies, indicating that anti-M-PLA2R could activate the lectin complement pathway [10,12]. Some scholars have found that the THSD7A existed in IMN patients with negative PLA2R [15,16,17]. This provides evidence to support that THSD7A antibodies cause MN. We investigated whether anti-THSD7A antibodies could cause MN in mice by activation of lectin complement pathway
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