Melatonin Alleviates Albumin-Induced Tubular Cell Injury by Activating Clock-Controlled Nuclear Enriched Abundant Transcript 1‑Mediated Proliferation

The pleiotropic and protective effects of melatonin have
been demonstrated
in a variety of animal models of renal injury. While coding RNAs regulated
by melatonin in renal tissues are well identified, the functional
involvement of long noncoding RNAs (lncRNAs) in melatonin signaling
remains undefined. This study identified nuclear enriched abundant
transcript 1 (NEAT1), a clock-controlled lncRNA that
was upregulated by melatonin through the BMAL1/CLOCK heterodimer in
renal tubular epithelial cells (TECs). Mechanistic studies showed
that melatonin enhanced NEAT1 expression via increasing
BMAL1 stability and thereby the enrichment of BMAL1 on NEAT1’s promoter. Further studies have
revealed that NEAT1 promotes the proliferation of
TECs by increasing levels of H3K27ac and H3K4me1 at the promoter regions
of the proliferation gene MKI67. Treatment of albumin-injured
TECs with melatonin promoted proliferation by transactivating NEAT1 and restoring the expression levels of core clock
genes and MKI67. Moreover, melatonin treatment ameliorated
proteinuria, hypoalbuminemia, and fibrotic lesions, which was correlated
with increased levels of core clock genes, H3K27ac, Mki67, and Neat1 in experimental MN kidneys. Melatonin
mediates a novel regulatory axis, BMAL1-NEAT1-MKI67, in TEC proliferation, establishing potential therapeutic
targets for MN and other renal diseases.