Abstract
Jian-Pi-Yi-Shen (JPYS), the traditional Chinese medicine (TCM) decoction, has been commonly used to treat chronic kidney disease (CKD) and its complications such as anemia. JPYS has been previously found to induce erythropoietin (EPO) production in HEK293T cells and CKD rats. However, the mechanism of JPYS in treating anemia of CKD rats has remained largely unknown. Here, we further extend our effort to investigate the translational control of hypoxia inducible factor- (HIF-) α protein via ERK signaling and the effect on iron recycling-related protein expression by JPYS, thus revealing the mechanism of JPYS in correcting anemia in CKD. Experimental CKD rats with anemia were induced by 5/6 nephrectomy. Rats were administrated orally with high dose (6.0 g/kg/d) and low dose (1.5 g/kg/d) of JPYS for 90 days. Serum hepcidin level was determined to evaluate iron homeostasis. The protein expressions of HIF-2α, erythropoietin (EPO), ferritin, and ferroportin (FPN) and the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) were detected by Western blot. The results showed that JPYS treatment significantly ameliorated kidney function by reducing increased levels of blood urea nitrogen (BUN), serum creatinine (Scr), and urine protein (UPRO). Periodic acid-Schiff (PAS) and Masson staining observation showed that the renal pathological damage was restored in JPYS-treated CKD rats. In parallel, JPYS markedly improved CKD anemia through upregulation of red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT). JPYS stimulated EPO and HIF-2α protein expressions in both the kidney and liver of CKD rats. Furthermore, JPYS induced the phosphorylation of ERK1/2 protein. In addition, JPYS regulated protein expression of ferritin and FPN in both the liver and spleen of CKD rats and the serum level of hepcidin. In conclusion, JPYS induces the expression of EPO through ERK-mediated HIF-2α protein accumulation and regulates systemic iron recycling, supporting its role in promoting erythropoiesis and improvement of anemia in CKD.
Highlights
Anemia is the most common complication of chronic kidney disease (CKD) [1, 2], and CKD anemia is associated with a poor quality of life and elevated cardiovascular mortality [3]
After 90 days of gavage, the levels of serum creatinine (Scr), blood urea nitrogen (BUN), and urine protein (UPRO) were significantly increased in the renal anemia group (RA) group compared with the sham group
We further found that the levels of Ca and P were significantly increased in the RA group compared with the sham group, and the levels of both were significantly reduced in JPYS-treated groups compared with the RA group (Supplementary Figure 2)
Summary
Anemia is the most common complication of chronic kidney disease (CKD) [1, 2], and CKD anemia is associated with a poor quality of life and elevated cardiovascular mortality [3]. The hypoxia inducible factor (HIF) as a transcription factor regulates 500–1000 gene expressions including EPO [6]. Accumulation of HIF-α protein plays crucial roles in increasing transcriptional activity of HIFregulated genes, resulting in induction of EPO expression. Functional iron deficiency due to inefficient utilization of iron stores can lead to the development of anemia in CKD patients [10]. The treatment of CKD patients who experienced anemia with erythropoiesis-stimulating agents (ESAs) has greatly improved their quality of life in clinical practice. For some CKD patients requiring dialysis, intravenous iron supplementation is needed for those who suffer from iron deficiency, yet its safety concerns remain [12]. For some CKD patients requiring dialysis, intravenous iron supplementation is needed for those who suffer from iron deficiency, yet its safety concerns remain [12]. erefore, it is still needed to find a more effective and safe approach for the treatment of CKD anemia
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