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.