p-Cresol, found at high concentrations in the serum of
chronic kidney failure patients, is known to cause cell senescence and other complications in different parts of the body.
p-Cresol is thought to mediate cytotoxic effects through the induction of autophagy response. However, toxic effects of
p-cresol on mesenchymal stem cells have not been elucidated. Thus, we aimed to investigate whether
p-cresol induces senescence of mesenchymal stem cells, and whether
melatonin can ameliorate abnormal autophagy response caused by
p-cresol. We found that
p-cresol concentration-dependently reduced proliferation of mesenchymal stem cells. Pretreatment with
melatonin prevented pro-senescence effects of
p-cresol on mesenchymal stem cells. We found that by inducing phosphorylation of Akt and activating the Akt signaling pathway,
melatonin enhanced
catalase activity and thereby inhibited the accumulation of
reactive oxygen species induced by
p-cresol in mesenchymal stem cells, ultimately preventing abnormal activation of autophagy. Furthermore, preincubation with
melatonin counteracted other pro-senescence changes caused by
p-cresol, such as the increase in total
5'-AMP-activated protein kinase expression and decrease in the level of phosphorylated mechanistic target of
rapamycin. Ultimately, we discovered that
melatonin restored the expression of senescence marker
protein 30, which is normally suppressed because of the induction of the autophagy pathway in
chronic kidney failure patients by
p-cresol. Our findings suggest that stem cell senescence in patients with
chronic kidney failure could be potentially rescued by the administration of
melatonin, which grants this
hormone a novel therapeutic role.