1.0 Introduction
Idiopathic nephrotic syndrome(INS) is the most prevalent kidney disease in children, and is a main cause of chronic renal failure in children in China[1]. It is characterized by the clinical manifestation of proteinuria, low plasma albumin, hyperlipidemia, and edema. The prevalence is mostly preschool children, and the peak period is 3-5 years old. About 80-90% of patients with kidney disease under 10 years of age are of minimal change disese (MCD)[2]. However, the specific etiology and mechanism of INS in children remains unclear. Previous studies have shown that the disease has obvious immune dysfunction, including humoral immune disorders, T cell subset dysfunction and abnormal secretion of cytokines, especially T cell dysfunction [3-8].
Th2 cells produce mainly IL-4、IL-5 and IL-13 and play an important role in parasitic infections and allergic inflammatory diseases[9-11]. As early as 1959, the association of pollen sensitivity and seasonal proteinuria has been reported, and about 30% of children with INS have atopic manifestations such as allergic rhinitis and idiopathic dermatitis[12]. Some studies have also confirmed that IgE in INS is increased during active phase[13-15], however, it is still uncertain whether increased levels of IgE in childhood INS are pathogenetic or coincident. The first hit consists of the induction of CD80 in podocytes by microbial products, allergen, or T-cell cytokines such as IL-13 act on the glomeruli, resulting in the overexpression of podocyte CD80 and temporary proteinuria[16-18]. In normal settings, CD80 expression on podocytes is terminated by regulatory cytokines from Tregulatory cells and/or cytotoxic T-lymphocyte-associated and IL-10 by podocytes, and as a consequence, proteinuria is transient and mild[18-20]. However, we propose a second hit occurs in MCD and consists of abnormal censoring of podocyte CD80 expression due to a defective autoregulatory response by Tregs or by the podocyte itself. As a consequence, CD80 expression becomes persistent and nephrotic syndrome results [20]. Th2 related cytokines IL-13, a known stimulator of IgE response, may mediate proteinuria in patients with MCD because of its ability to directly induce CD80 expression on the podocyte[13-15, 18]. In recent years, studies have found that IL-13 and IL-4 were increased during the active phase of INS, IL-13 has involved in the pathogenesis of kidney disease[13-15, 18], but the mechanisms resulting in IL-13 increasing was still unclear. A few studies have also noticed that Th2 cells were over-activation in INS[8,18, 21-22], but the mechanisms resulting in Th2 cells over activation remained unknown, which needed to be studied to further explain the pathogenesis of INS immune.
MicroRNAs (miRNAs or miRs) are short non-coding RNAs of 20-23 nucleotides that regulate target gene expression in a post-transcriptional manner [23-24]. In brief, microRNAs can bind to the 3’-untranslated region (3’-UTR) of target mRNAs, leading to their translational inhibition or degradation [23-24]. Previously, miRNAs appeared more in the field of cancer and tumor research. Recently, miRNAs have also received much attention in kidney disease. Studies have shown that multiple miRNAs can inhibit the differentiation and function of Th2 cells[25-27]. In 2016, some scholars discovered that miR-24 and miR-27 act collaboratively through different downstream pathways to inhibit Th2 cell differentiation and IL-4 production [26-27]. However, it is unclear whether changes in miRNAs expression alter Th2 expression in active non-atopic INS, and its specific mechanism of action needs to be further study.
Therefore, in this study we systematically observes the dynamic changes of cytokines and miR-24, miR-27 involved in regulating Th2 cell differentiation in the active and remission phases, and observes the changes in the number and function of Th2 cells in children with non-atopic INS under different miRNAs expression. It may clarify the immune pathogenesis in INS, which may provide potential therapeutic targets and new ideas for the treatment of kidney disease.