Salidroside stimulates the accumulation of HIF-1α protein resulted in the induction of EPO expression: A signaling via blocking the degradation pathway in kidney and liver cells

Rhodiolae Crenulatae Radix et Rhizoma (Rhodiola), the root and rhizome of Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba, has been used as a traditional Chinese medicine (TCM) to increase the body resistance to mountain sickness in preventing hypoxia; however, the functional ingredient responsible for this adaptogenic effect has not been revealed. Here, we have identified salidroside, a glycoside predominantly found in Rhodiola, is the chemical in providing such anti-hypoxia effect. Cultured human embryonic kidney fibroblast (HEK293T) and human hepatocellular carcinoma (HepG2) were used to reveal the mechanism of this hematopoietic function mediated by salidroside. The application of salidroside in cultures induced the expression of erythropoietin (EPO) mRNA from its transcription regulatory element hypoxia response element (HRE), located on EPO gene. The application of salidroside stimulated the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein, but not HIF-2α protein: the salidroside-induced HIF-1α protein was via the reduction of HIF-1α degradation but not the mRNA induction. The increased HIF-1α could account for the activation of EPO gene. These results supported the notion that hematopoietic function of Rhodiola was triggered, at least partially, by salidroside. A proposed mechanism for salidroside-induced the expressions of EPO gene in kidney and liver cells. Salidroside-induced EPO expression is mediated by HIF-1α, but not HIF-2α, that triggers the transcription of EPO gene via HRE regulatory element. Salidroside can accumulate HIF-1α protein via blocking the protein degradation pathway, possibly at the stage of blocking the hydroxylation of HIF-1α. However, salidroside cannot affect the transcriptional level of HIF-1α. [Display omitted]