Membranous nephropathy (MN), a type of glomerular nephritis, is one of the most common causes of nephrotic syndrome in adults. Although it is known that melatonin plays a protective role in MN, the role of melatonin receptors in the pathophysiology of MN is unclear. Using an experimental MN model and clinical MN specimens, we studied melatonin receptor expression and found that melatonin receptor 1A (MTNR1A) expression was significantly downregulated in renal tubular epithelial cells. Molecular studies showed that the transcription factor pituitary homeobox‐1 (PITX1) promoted MTNR1A expression via direct binding to its promoter. Treatment of a human tubular cell line with albumin to induce injury resulted in the stable reduction in MTNR1A and PITX1 expression. PITX1 levels were significantly downregulated in tubular epithelial cells from mice MN kidneys and MN renal specimens. Knockdown of MTNR1A, PITX1, or cyclic adenosine monophosphate‐responsive element‐binding protein (CREB) decreased E‐cadherin (CDH1) expression, but upregulated Per2 and α‐smooth muscle actin (αSMA) expression. Blockade of the MTNR1A receptor with luzindole in MN mice further impaired renal function; this was accompanied by CDH1 downregulation and Per2 and αSMA upregulation. Together, our results suggest that in injured tissue, decreased PITX1 expression at the MTNR1A promoter regions leads to decreased levels of MTNR1A in renal tubular epithelial cells, which increases the future risk of MN.

中文翻译：

---

褪黑素受体1A和垂体同源盒1的共表达在保护膜性肾病中的肾小管上皮细胞中的作用

膜性肾病（MN）是一种肾小球性肾炎，是成人肾病综合征最常见的原因之一。尽管已知褪黑激素在MN中起保护作用，但是尚不清楚褪黑激素受体在MN的病理生理中的作用。使用实验的MN模型和临床MN标本，我们研究了褪黑激素受体的表达，发现褪黑素受体1A（MTNR1A）的表达在肾小管上皮细胞中显着下调。分子研究表明，转录因子垂体同源盒-1（PITX1）促进了MTNR1A通过直接与其启动子结合而表达。用白蛋白处理人肾小管细胞系以诱导损伤，导致MTNR1A和PITX1表达稳定下降。在小鼠MN肾和MN肾标本中，肾小管上皮细胞中的PITX1水平显着下调。敲低MTNR1A，PITX1或环状腺苷单磷酸反应性元素结合蛋白（CREB）会降低E-钙黏着蛋白（CDH1）的表达，但会上调Per2和α-平滑肌肌动蛋白（αSMA）的表达。MN小鼠中用luzindole阻断MTNR1A受体会进一步损害肾功能；这伴随着CDH1的下调以及Per2和αSMA的上调。总之，我们的结果表明，在受伤的组织中，MTNR1A启动子区域PITX1表达的降低导致肾小管上皮细胞MTNR1A的水平降低，