Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review)

Abstract

Endogenous melatonin is synthesized at night by specific enzymes and exerts various physiological effects through both melatonin receptor-dependent and -independent pathways. Moreover, exogenous melatonin has been demonstrated to have pleiotropic therapeutic effects on a range of pathological conditions, including renal diseases. The melatonin signaling pathway involves specific enzymes responsible for melatonin synthesis and cellular responses mediated by melatonin, which are evolutionarily conserved in both brain and peripheral tissues. Although the physiological functions of the melatonin-mediated signaling pathway are well-documented across multiple organ systems, its effects on the kidney are less recognized. The present review summarizes the expression levels of melatonin biosynthesis enzymes and melatonin receptors, as well as their roles in renal tissue under pathological conditions such as membranous nephropathy (MN). The present review explores the molecular mechanisms regulating the expression of aryl-alkyl-amine N-acetyl-transferase, nuclear enriched abundant transcript 1 and melatonin receptor 1A (MTNR1A) in renal tubular epithelial cells. Overall, the present review provides new insights into the role of MTNR1A in the pathology, treatment and prevention of MN.

Keywords: AANAT; MN; MTNR1A; NEAT1; melatonin; renal TECs.

Figure 1

Diagrammatic representation of the melatonin synthesis pathway and melatonin receptor-mediated cell signaling. The metabolic pathway converting tryptophan to melatonin involves the enzymes TPH, DDC, AANAT and HIOMT (also known as ASMT). Melatonin activation of MTNR1A receptors triggers Gq activation, leading to increased levels of calcium and IP3. Additionally, it induces Gi-dependent activation of the PI3K/AKT and PKC/ERK pathways, while causing Gi-dependent inactivation of the PKA/CREB axis. MTNR1B coupling to Gi results in PKG inactivation and a decrease in intracellular cGMP levels. TPH, tryptophan hydroxylase; DDC, aromatic amino acid decarboxylase; AANAT, aryl-alkyl-amine N-acetyltransferase; HIOMT, hydroxy-indole-O-methyl-transferase; MTNR1A, melatonin receptor 1A; MTNR1B, melatonin receptor 1B; PKC, protein kinase C; cGMP, 3'-5'-cyclic guanosine monophosphate; PKG, protein kinase G; IP3, inositol 1,4,5-triphosphate; PLCb, phospholipase C beta.

Figure 2

A comprehensive tissue-specific analysis of melatonin synthesis enzyme gene expression across 37 tissues. Transcripts per million on the y-axis represents the transcript quantification value, while the x-axis represents different tissues. This data is based on The Human Protein Atlas version 18.1 and Ensemble version 88.38(21). TPH, tryptophan hydroxylase; DDC, aromatic amino acid decarboxylase; AANAT, aryl-alkyl-amine N-acetyltransferase; HIOMT, hydroxy-indole-O-methyl-transferase.

Figure 3

Schematic representation illustrates the molecular mechanism regulating MTNR1A, NEAT1 and AANAT gene expression in renal TECs. PITX1 transcriptionally upregulates MTNR1A expression, while c-Fos transcriptionally downregulates AANAT expression in the nucleus. AANAT is the rate-limiting factor for melatonin synthesis. Albumin treatment reduced the viability of TECs by decreasing PITX1 and increasing c-Fos. In the cytosol, hnRNPL binds to MTNR1A transcripts via CA-repeat elements, decreasing MTNR1A degradation by EXOSC10. Melatonin binding to MTNR1A triggers upregulation of HO-1 levels and downregulation of cAMP levels, phosphorylated CREB and PER2. Luzindole, an MTNR1A antagonist, decreased the MTNR1A-mediated signaling pathway. The long noncoding RNA NEAT1 is increased by melatonin and exhibits circadian rhythm in TECs through whole gene identification. Melatonin enhances clock-controlled NEAT1 expression in TECs by stabilizing the BMAL1 protein. Elevated clock-controlled NEAT1 may regulate circadian genes, including MKI67, by influencing H3K27Ac and H3K4me1 occupancy at enhancer regions of target genes. Genomic location of MTNR1A single nucleotide polymorphism rs374152717 (*), a donor splice site variant in intron 1 near exon 1. MTNR1A, melatonin receptor 1A; NEAT1, nuclear enriched abundant transcript 1; AANAT, aryl-alkyl-amine N-acetyltransferase; TECs, tubular epithelial cells; PITX1, pituitary homeobox-1; hnRNPL, heterogeneous nuclear ribonucleoprotein L; HO-1, heme oxygenase-1; cAMP, cyclic adenosine monophosphate; CREB, cAMP responsive element binding protein; EXOSC10, exosome component 10.

Figure 4

Schematic diagram illustrates the circadian rhythm of gene expression levels in the mouse kidney. The peaks in the diagram indicate maximum expression levels, and the dips indicate minimum expression levels, thus representing the period and amplitude of each gene's oscillation. The upper portion of the figure illustrates the patterns of MTNR1A mRNA (pink line) and NEAT1 transcripts (red line). The lower portion shows the patterns of pCREB (orange line), PITX1 protein (blue line) and hnRNPL (green line). The thickness of the line is positively associated with the gene levels. The x-axis indicates Zeitgeber time (ZT). MTNR1A, melatonin receptor 1A; NEAT1, nuclear enriched abundant transcript 1; CREB, cAMP responsive element binding protein; pCREB, phosphorylated CREB; PITX1, pituitary homeobox-1; hnRNPL, heterogeneous nuclear ribonucleoprotein L.