The Non-Coding RNA Landscape in IgA Nephropathy-Where Are We in 2021?

Abstract

IgA nephropathy (IgAN) is the most commonly diagnosed primary glomerulonephritis worldwide. It is a slow progressing disease with approximately 30% of cases reaching end-stage kidney disease within 20 years of diagnosis. It is currently only diagnosed by an invasive biopsy and treatment options are limited. However, the current surge in interest in RNA interference is opening up new horizons for the use of this new technology in the field of IgAN management. A greater understanding of the fundamentals of RNA interference offers exciting possibilities both for biomarker discovery and, more importantly, for novel therapeutic approaches to target key pathogenic pathways in IgAN. This review aims to summarise the RNA interference literature in the context of microRNAs and their association with the multifaceted aspects of IgA nephropathy.

Keywords: IgA nephropathy; RNA interference; microRNA.

Figure 1

RNA interference. The influence non-coding RNAs have on mRNA once it has been transcribed from its gene on its journey to the ribosome for translation into protein.

Figure 2

Biogenesis of microRNAs. MicroRNAs are transcribed from the non-coding regions of the genome by the actions of RNA polymerase 2. The resultant hairpin-looped primary miR (pri-miR) undergoes post-transcriptional editing by the actions of the RNAse Drosha, supported by the action of DGCR8 which cleaves the pri-miR at its 5’ and 3’ regions to produce a precursor miR (pre-miR). The pre-miR is exported out of the nucleus by the Exportin 5-Ran-GTP complex, which also protects it from degradation. The pre-miR undergoes further editing by the actions of Dicer, which cleaves off the hairpin loop structure to generate short double stranded microRNA. The two miR strands are separated by helicases. The less thermodynamically stable ‘guide’ strand is loaded onto the argonaute protein within the RNA-induced silencing complex (RISC). The remaining ‘passenger’ strand is cleaved and degraded in the cytoplasm. The RISC is then guided to its target site on mRNA where, depending on complementarity, it will degrade the mRNA or disrupt its translation.

Figure 3

Intrarenal miR interactions. This diagram illustrates the result of dysregulated miR interactions on the cells of the nephron leading to inflammation and fibrosis. For clarity, only some of the major interactions have been described. IgA deposition downregulates miRs -16, -100 and -877 in mesangial cells, which induces the generation of cytokines IL-6, IL-8 and IL-1β. Subsequently, IL-8 upregulates expression of miR-21 in tubular cells and downregulates E-cadherin as part of the process of epithelial–mesenchymal transition (EMT)—a hallmark of fibrosis. IL-1β upregulates miR-21 expression in podocytes reducing phosphatase and tensin homologue (PTEN) expression and inducing podocyte effacement. IL-6 downregulates miR-223 expression in endothelial cells causing proliferation and expression of intracellular adhesion molecule (ICAM1). In the tubular cells, TGB-β downregulates expression of miRs-200c, -192 and -29c which induces EMT by reducing E-cadherin and increasing collagen deposition.

Figure 4

MicroRNAs which modulate IgA1 O-glycosylation. The process of IgA hinge region O-glycosylation is initiated by attachment of N-acetyl galactosamine (GalNAc) to a serine or threonine amino acid by the actions of N-acetyl-galactosamine transferase 2 (GalNAc T2). Galactose is sequentially attached by core 1 β,3-galactosyltransferase (C1GalT1) with the aid of its chaperone protein COSMC. N-acetyl neuraminic acid (NANA) can then be added to galactose by the actions of β-galactoside α-2,3 sialyl transferase 1 (ST3Gal1) for linkage in the α 2-3 orientation or to N-acetylgalactosamine by α-N-acetylgalactosaminide sialyl transferase 2 (ST6 GalNAc 2) for linkage in the α2-6 orientation. However, miR-let-7b can prevent the addition of GalNAc to its hydroxylated amino acid. MiR-148 and miR-98 can reduce the activity of C1GalT1, thereby reducing the binding of galactose to GalNAc. MiRs -320 and -374 can downregulate COSMC, reducing the ability of C1GalT1 to galactosylate N-acetyl galactosamine. Consequently, ST6GalNAc 2 can add NANA to the naked GalNAc sugar residue, preventing further extension of the sugar chain resulting in less O-galactosylation of IgA.