Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

Abstract

Background: Immunoglobulin (Ig) A nephropathy (IgAN) is the finding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Increasing evidence suggested that retinoic acid (RA) signaling selectively induces IgA isotype switching and basic leucine zipper transcription factor, ATF-like (BATF) controls the global regulators of class switch recombination (CSR) in lymphocytes. Great effort has been paid to identify whether impaired immune regulation along the ‘mucosa-bone marrow (BM) axis' play an important role in the pathogenesis of IgAN. Methods: The aim of the study was to investigate the expression of all-trans-RA (ATRA) and BATF, and to identify their impact on IgA CSR in IgAN patients and rat animal models. Blood samples and tonsillar tissue specimens were obtained from 22 patients with IgAN and 24 patients with chronic tonsillitis as control. Results: Immunohistochemical, RT-PCR and western blotting examination revealed that RA signaling and BATF productions are activated in IgAN patients compared with controls. Lipopolysaccharide and α-hemolytic streptococcus stimulation upregulated RA receptor (RAR) and BATF expression, promote IgA CSR and ATRA productions in tonsil mononuclear cells. RAR alpha (RARα) or BATF siRNA decreases IgA expression. We also built IgAN rat models and found that RARα, BATF and activation-induced cytidine deaminase were upregulated in the peripheral blood, spleen and BM. With ATRA (500 μg/kg body weight) treatment for 8 weeks, IgA deposition on glomeruli and mesangial cells proliferation increased. It also revealed that ATRA activated BATF and IgA CSR in vivo. Conclusion: These data point toward the role of RA signaling together with BATF in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with neoantigen results in impaired mucosal and systemic IgA responses.

Protective effect of retinoic acid receptor α on hypoxia‐induced epithelial to mesenchymal transition of renal tubular epithelial cells associated with TGF‐β/MMP‐9 pathway

“…As a nuclear retinoic acid receptor, RARa plays multiple roles in biological processes, including organogenesis (Mendelsohn et al, 1999), homeostasis (Canete et al, 2017), and tumor metastasis (Doi et al, 2015). Furthermore, RARa is connected with kidney diseases, such as HIVassociated nephropathy (Ratnam et al, 2011), Ig A nephropathy (He et al, 2016), and crescentic glomerulonephritis (Dai et al, 2017). Most recently, RARa has been suggested to mediate ECM deposition in the progression of RIF in vitro and in vivo (Long et al, 2012;Chen et al, 2017a).…”

“…For example, studies conducted by He et al () and Ratnam et al () suggested that activation of RARα protected against the development of HIV‐associated nephropathy. He et al () later found that RARα was involved in the immunoglobulin class switch recombination of IgA nephropathy. In addition, our previous studies have shown that RARα exerts anti‐fibrotic effects on tubulointerstitial fibrosis, because it is associated with matrix deposition and degradation in fibrotic kidneys (Long et al, ).…”

Rapamycin Enhances Repressed Autophagy and Attenuates Aggressive Progression in a Rat Model of IgA Nephropathy

“…Tissue samples were prepared as previously described [27,28,29]. Renal cortex tissue was lysed in RIPA Lysis Buffer (Beyotime Biotechnology).…”

Levels of Apelin-12, AT1R, and AGT are correlated with degree of renal fibrosis in patients with immunoglobulin A nephropathy

“…Immunoglobulin A (IgA) nephropathy (IgAN) is a kind of immune complex nephritis in which IgA deposits in the mesangial area of the glomerulus (1)(2)(3). IgAN is the most prevalent primary glomerular disease worldwide and in China, IgAN patients account for about 45% of primary glomerular disease (4)(5)(6)(7). Studies have shown that renal fibrosis is an important factor affecting the progression and prognosis of IgAN (8,9).…”