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

  • Authors:
    • Yen-Sung Huang
    • Shuk-Man Ka
    • Kuo-Cheng Lu
    • Ann Chen
    • Chia-Chao Wu
  • View Affiliations / Copyright

    Affiliations: Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan, Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei 114201, Taiwan, Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231016, Taiwan, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970473, Taiwan, Division of Nephrology, Department of Internal Medicine, Tri‑Service General Hospital, National Defense Medical Center, Taipei 114202, Taiwan
    Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 139
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    Published online on: June 12, 2025
       https://doi.org/10.3892/br.2025.2017
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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.
View Figures

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.
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Copy and paste a formatted citation
Spandidos Publications style
Huang Y, Ka S, Lu K, Chen A and Wu C: Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review). Biomed Rep 23: 139, 2025.
APA
Huang, Y., Ka, S., Lu, K., Chen, A., & Wu, C. (2025). Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review). Biomedical Reports, 23, 139. https://doi.org/10.3892/br.2025.2017
MLA
Huang, Y., Ka, S., Lu, K., Chen, A., Wu, C."Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review)". Biomedical Reports 23.2 (2025): 139.
Chicago
Huang, Y., Ka, S., Lu, K., Chen, A., Wu, C."Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review)". Biomedical Reports 23, no. 2 (2025): 139. https://doi.org/10.3892/br.2025.2017
Copy and paste a formatted citation
x
Spandidos Publications style
Huang Y, Ka S, Lu K, Chen A and Wu C: Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review). Biomed Rep 23: 139, 2025.
APA
Huang, Y., Ka, S., Lu, K., Chen, A., & Wu, C. (2025). Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review). Biomedical Reports, 23, 139. https://doi.org/10.3892/br.2025.2017
MLA
Huang, Y., Ka, S., Lu, K., Chen, A., Wu, C."Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review)". Biomedical Reports 23.2 (2025): 139.
Chicago
Huang, Y., Ka, S., Lu, K., Chen, A., Wu, C."Therapeutic insights and molecular mechanism linking melatonin signaling and membranous nephropathy (Review)". Biomedical Reports 23, no. 2 (2025): 139. https://doi.org/10.3892/br.2025.2017
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