Melatonin ameliorates renal fibroblast‐myofibroblast transdifferentiation and renal fibrosis through miR‐21‐5p regulation

Abstract

Fibroblast‐myofibroblast transdifferentiation (FMT) is widely recognized as the major pathological feature of renal fibrosis. Although melatonin has exerted antifibrogenic activity in many diseases, its role in renal FMT remains unclear. In the present study, the aim was to explore the effect of melatonin on renal FMT and the underlying mechanisms. We established the transforming growth factor (TGF)‐β1 stimulated rat renal fibroblast cells (NRK‐49F) model in vitro and unilateral ureteral obstruction (UUO) mice model in vivo. We assessed levels of α‐smooth muscle actin (α‐SMA), col1a1 and fibronectin, STAT3 and AP‐1, as well as miR‐21‐5p and its target genes (Spry1, PTEN, Smurf2 and PDCD4). We found that melatonin reduced the expression of α‐SMA, col1a1 and fibronectin, as well as the formation of α‐SMA filament in TGF‐β1‐treated NRK‐49F cells. Meanwhile, melatonin inhibited STAT3 phosphorylation, down‐regulated miR‐21‐5p expression, and up‐regulated Spry1 and PTEN expression. Moreover, miR‐21‐5p mimics partially antagonized the anti‐fibrotic effect of melatonin. For animal experiments, the results revealed that melatonin remarkably ameliorated UUO‐induced renal fibrosis, attenuated the expression of miR‐21‐5p and pro‐fibrotic proteins and elevated Spry1 and PTEN expression. Nevertheless, agomir of miR‐21‐5p blocked the renoprotective effect of melatonin in UUO mice. These results indicated that melatonin could alleviate TGF‐β1‐induced renal FMT and UUO‐induced renal fibrosis through down‐regulation of miR‐21‐5p. Regulation of miR‐21‐5p/PTEN and/or miR‐21‐5p/Spry1 signal might be involved in the anti‐fibrotic effect of melatonin in the kidneys of UUO mice.

Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases

“…In addition, we previously demonstrated that a melatonin treatment can suppress renal fibrosis by upregulating miR-4516 in kidney tissues [139], and this is consistent with the widely reported antifibrotic effects of melatonin [140,141,201,202]. More recently, we showed that the melatonin-mediated upregulation of miR-4516 promotes PrP C expression [68].…”

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

“…Renal fibroblasts quiescently reside in renal interstitium and play an essential role in ECM homeostasis for maintaining the kidney ultrastructure and function 61 , 62 . During fibrogenesis, the quiescent fibroblasts are activated and display a spindle-shaped, mesenchymal phenotype, known as myofibroblasts 63 , 64 . In the present study, we found that BHK-21 cells treated with COM-MP secretome were more spindle-shaped and had greater spindle index, indicating that they underwent activation into myofibroblasts.…”

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

“…A major marker of PSC activation is the expression of α-sma [ 63 ]. Interestingly, melatonin decreases the expression of this protein in myofibroblasts [ 64 ], endothelial cells [ 65 ], liver [ 66 ] or lung [ 67 ]. These observations support an antifibrogenic action of melatonin in these tissues.…”