Role of melatonin receptor 1A and pituitary homeobox‐1 coexpression in protecting tubular epithelial cells in membranous nephropathy

Abstract

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.

MiR-130a-5p prevents angiotensin II-induced podocyte apoptosis by modulating M-type phospholipase A2 receptor

“…All mice received cationic bovine serum albumin (0.2 mg, cBSA) emulsified in complete Freund's adjuvant (CFA) (Sigma-Aldrich, St. Louis, MO, USA) [19]. Two weeks later, the mice in MN, MN+ agomir-miR-130a-5p and MN+ agomir-NC groups were intravenously injected with cBSA (100 μg) three times per week (every other day) for 6 weeks, and the control mice received pure saline on the same schedule [20]. For agomir-miR-130a-5p and agomir-NC administration, MN mice received agomir-miR-130a-5p or agomir-NC (0.2 mg/mouse) on days 0, 3, 7, and 14 of MN induction.…”

The krüppel‐like factor Dar1 restricts the proliferation of Drosophila intestinal stem cells

“…Among the four types of midgut cells, only ISCs can divide. Following one round of asymmetric cell division, one ISC generates two daughter cells; one of them can still keep the stem cell identity (self‐renewal) and the other starts differentiation to become either an EC through the intermediate EB (high Notch activity ), or become an EE progenitor (high Scute activity) that will divide one more time to generate a pair of EE cells .…”

The MTNR1A mRNA is stabilized by the cytoplasmic hnRNPL in renal tubular cells

“…For diurnal rhythms, BALB/c mice were killed by decapitation at set intervals, beginning at light onset (i.e., at ZT0, ZT4, ZT8, ZT12, ZT16, ZT20, and ZT24) (n = 3 per group). The experimental MN model was induced as described previously (Huang et al, 2018;Wu et al, 2008Wu et al, , 2015Wu, Lu, Lin, & Hsieh, 2012). BALB/c mice received cationic bovine serum albumin (cBSA; Chondrex, Redmond, WA) intravenously three times per week (every other day) for 6 weeks, and the control (Ctrl) mice received pure saline on the same schedule.…”

“…Immunohistochemistry was performed as described previously (Huang et al, 2018;Wu et al, 2008Wu et al, , 2015 and counterstained using haematoxylin. The stained slides were scanned on a Panoramic 250 digital scanner (3DHISTECH Ltd., Budapest, Hungary).…”

“…Moreover, MTNR1A levels downregulation in tubular epithelial cells increases the severity of experimental MN (Huang et al, 2018). While the distribution of MTNR1A in renal tubular epithelial cells has been well studied, the regulation of its density has been examined poorly.…”