Abstract
IgA nephropathy (IgAN) is the most common primary glomerular disease. The characteristic pathology involves immune complexes formed by the deposition of IgA1 and underglycosylated IgA1 aggregates in the mesangial area, which may be accompanied by the deposition of IgG and/or IgM and complement components. However, the molecular mechanisms of IgAN remain unclear. In the present study, microarray analysis showed that the expression of microRNA-630 (miR-630) was significantly reduced in palatal tonsils from IgAN patients compared with chronic tonsillitis. Additionally, bioinformatic analysis showed that Toll-like receptor 4 (TLR4) was the predicted target gene of miR-630 and was regulated by miR-630. When miR-630 was overexpressed in palatal tonsil mononuclear cells from IgAN patients, the expression of TLR4 was reduced and the content of IgA1 in the cell culture supernatant was decreased, and the level of galactosylation in the IgA1 hinge region was increased. Moreover, immunohistochemical analysis showed that the expression of TLR4 in IgAN patients was significantly increased. After knocking down the expression of TLR4, both the concentration of IgA1 and the binding force of IgA1 with broad bean lectin were significantly reduced in IgAN. Furthermore, the mechanism study demonstrated that TLR4 might regulate the expression of IL-1β and IL-8 through NF-κB signaling pathway to modulate the concentration of IgA1 and the glycosylation level of IgA1. This interesting finding may offer new insight into the molecular mechanism of IgAN.
Highlights
IgA nephropathy (IgAN) is considered the most common form of primary glomerulonephritis throughout the world [1], and more than 40% patients with IgAN develop into end-stage renal disease (ESRD) within 20–25 years [2]
The Quantitative Reverse TranscriptionPolymerase Chain Reaction (qRT-PCR) results showed that miR-630, miR-513b, miR-135a3p, and miR-642a-3p were significantly decreased in the IgAN group compared with the CT group; the decrease in the expression of miR-630 was the most significant (Figure 1B)
The Pearson’s correlation analysis showed that the levels of miR-630 in tonsils were positively correlated with estimated glomerular filtration rate and albumin (ALB), but negatively correlated with creatinine (Cre), proteinuria, and hematuria (Figures 1D–H)
Summary
IgA nephropathy (IgAN) is considered the most common form of primary glomerulonephritis throughout the world [1], and more than 40% patients with IgAN develop into end-stage renal disease (ESRD) within 20–25 years [2]. Our previous study demonstrated that serum IgA levels were significantly lower in tonsillectomized cases compared to non-tonsillectomized patients; hematuria as well as proteinuria were decreased greatly [10, 11]. These data suggested that the deposition of underglycosylated IgA1 in the mesangial region of IgAN was partially produced by the tonsil. Focusing on the study of palatal tonsil immune response disorders in IgAN may be helpful to elucidate the mechanism of the production of underglycosylated IgA1 in IgAN patients
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