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 (<i>NEAT</i>1), 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 <i>NEAT</i>1 expression via increasing BMAL1 stability and thereby the enrichment of <i>BMAL</i>1 on <i>NEAT</i>1's promoter. Further studies have revealed that <i>NEAT</i>1 promotes the proliferation of TECs by increasing levels of H3K27ac and H3K4me1 at the promoter regions of the proliferation gene <i>MKI</i>67. Treatment of albumin-injured TECs with melatonin promoted proliferation by transactivating <i>NEAT</i>1 and restoring the expression levels of core clock genes and <i>MKI</i>67. Moreover, melatonin treatment ameliorated proteinuria, hypoalbuminemia, and fibrotic lesions, which was correlated with increased levels of core clock genes, H3K27ac, <i>Mki</i>67, and <i>Neat</i>1 in experimental MN kidneys. Melatonin mediates a novel regulatory axis, BMAL1-<i>NEAT</i>1-<i>MKI</i>67, in TEC proliferation, establishing potential therapeutic targets for MN and other renal diseases.