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Previous studies have revealed abnormal lymphocyte subsets in IgA nephropathy (IgAN). Some microRNAs have been reported to influence T helper differentiation. Here, we explored the underlying mechanism regarding how miRNAs regulate lymphocyte subsets in IgAN. First, miRNA and mRNA profiles in PBMCs from IgAN patients and controls were obtained by next-generation sequencing and gene expression array. The target miRNAs and mRNAs were identified through combined analysis. Then, in an independent population, we detected the expression of target miRNA in CD3+ T cells and CD19+ B cells. Next, we detected T helper cell subgroups and plasma IgA1 levels in another independent population and analyzed the correlations between them. In total, 22 differentially expressed miRNAs were identified between IgAN patients and controls. Among them, microRNA-21-5p (miR-21) showed the highest expression, and SPRY1, SPRY2, and FASLG were chosen as miR-21 target genes. Then, we confirmed elevated miR-21 levels in CD3+ T cells of IgAN patients. Accordingly, decreased mRNA levels of SPRY1, SPRY2, and FASLG were found, and miR-21 showed a significant negative correlation with SPRY1 levels in CD3+ T cells of IgAN patients. Finally, we revealed that the proportion of Th17 cells was significantly elevated in IgAN patients and negatively correlated with SPRY1 expression. Furthermore, the proportion of Th17 cells showed a positive correlation trend with plasma IgA1 levels. Our results suggested that in IgAN, the upregulated miR-21 expression in T lymphocytes inhibited SPRY1 expression and thereby induced Th17 polarization, which might influence the characteristic feature of IgA1 overproduction in IgAN patients.

Background Immunoglobulin A (IgA) vasculitis with nephritis (IgAVN) and IgA nephropathy (IgAN) are widely considered as related diseases. Considerable evidences support the notion of involvement of complement activation in both IgAVN and IgAN. Our previous studies identified a genetic variant in complement factor H (CFH), rs6677604, as an IgAN-susceptible variant by genome-wide association study, and further confirmed its linkage to CFHR3-1Δ and proved its influence on complement activation and thereby on IgAN susceptibility. Aim To explore the role of rs6677604 in complement activation of IgAVN. Methods In this study, we enrolled 632 patients with IgAVN, 1178 patients with IgAN and 902 healthy controls. The genotype of rs6677604 was measured by TaqMan allele discrimination assays or was extracted from genome-wide association study data. Results The frequency of the rs6677604-A allele was significantly higher in IgAVN than in IgAN. However, no significant differences were observed between IgAVN and the controls. Higher complement factor H (FH) levels were observed in IgAVN than IgAN, and positive correlation between circulating FH and C3 levels was present in IgAVN. In both IgAVN and IgAN, rs6677604-A was associated with less intensity of glomerular C3 deposits. In agreement with the higher frequency of rs6677604-A in IgAVN, the glomerular C3 deposits of patients with IgAVN were less intense than those in IgAN. Conclusion Our findings suggest that genetic variation in CFH (rs6677604) is involved in the phenotype of complement activation in both IgAVN and IgAN. Moreover, rs6677604 might contribute to the difference of complement activation intensity between IgAVN and IgAN.

Background and objectives IgA nephropathy is the most common primary GN worldwide. Previous research demonstrated that collectin11, an initiator of the complement lectin pathway, was involved in both AKI and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy. Design, setting, participants, & measurements The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. In vitro, human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by quantitative RT-PCR and immunofluorescence. The codeposition of collectin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays. Results In total, 37% of participants with IgA nephropathy (22 of 60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface via the interaction with deposited IgA1-immune complexes. In vitro, we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells. Conclusions In situ–produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.

Background Immunoglobulin A nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. Previous studies have proved that renal-deposited IgA in IgAN came from circulating IgA1-containing complexes (CICs). Methods To explore the composition of CICs in IgAN, we isolated CICs from IgAN patients and healthy controls and then quantitatively analyzed them by mass spectrometry. Meanwhile, the isolated CICs were used to treat human mesangial cells to monitor mesangial cell injury. Using the protein content and injury effects, the key constituent in CICs was identified. Then the circulating levels of identified key constituent–IgA complex were detected in an independent population by an in-house-developed enzyme-linked immunosorbent assay. Results By comparing the proteins of CICs between IgAN patients and controls, we found that 14 proteins showed significantly different levels. Among them, α1-microglobulin content in CICs was associated with not only in vitro mesangial cell proliferation and monocyte chemoattractant protein 1 secretion, but also in vivo estimated glomerular filtration rate (eGFR) levels and tubulointerstitial lesions in IgAN patients. Moreover, we found α1-microglobulin was prone to bind aberrant glycosylated IgA1. Additionally, elevated circulating IgA-α1-microglobulin complex levels were detected in an independent IgAN population and IgA-α1-microglobulin complex levels were correlated with hypertension, eGFR levels and Oxford T- scores in these IgAN patients. Conclusions Our results suggest that the IgA-α1-microglobulin complex is an important constituent in CICs and that circulating IgA-α1-microglobulin complex detection might serve as a potential noninvasive biomarker detection method for IgAN.

Biomechanical factors play an extremely important role in regulating the function of articular chondrocytes. Understanding the mechanical factors that drive chondrocyte biological responses is at the heart of our interpretation of cascade events leading to changes in articular cartilage osteoarthritis. The mechanism by which mechanical load is transduced into intracellular signals that can regulate chondrocyte gene expression remains largely unknown. The mechanically sensitive ion channel (MSC) may be one of its specific mechanisms. This review focuses on four ion channels involved in the mechanotransduction of chondrocytes, exploring their properties and the main factors that activate the associated pathways. The upstream and downstream potential relationships between the protein pathways were also explored. The specific biophysical mechanism of the chondrocyte mechanical microenvironment is becoming the focus of research. Elucidating the mechanotransduction mechanism of MSC is essential for the research of biophysical pathogenesis and targeted drugs in cartilage injury-related diseases.