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.