Jian‐Pi‐Yi‐Shen Regulates EPO and Iron Recycling Protein Expressions in Anemic Rats with Chronic Kidney Disease: Accumulation of Hypoxia Inducible Factor‐2α via ERK Signaling

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.

A Bioinformatics Model of Human Diseases on the Basis of Differentially Expressed Genes (of Domestic Versus Wild Animals) That Are Orthologs of Human Genes Associated with Reproductive-Potential Changes

“…Human gene HBB codes for hemoglobin subunit β, whose deficit (thalassemia) worsens women’s reproductive health [ 81 ], in agreement with the direction of expression change of the dog orthologous gene—deficit during microevolution [ 28 ] ( Table 4 ). Conversely, in traditional Chinese medicine, the Jian-Pi-Yi-Sheng decoction (JPYS) is employed to raise the HBB level for treating anemia in chronic kidney diseases [ 82 ]…”

Cell-Based Biological Markers for Blood-Enriching Chinese Herbs: Erythropoietin Production in HepG2 Cells and Nitric Oxide Release in Human Umbilical Vein Endothelial Cells (HUVECs)

“…In this regard, three HIF-α prolyl hydroxylases can initiate proteasomal degradation of HIF-α, thereby suppressing EPO production [19]. It has been demonstrated that a Chinese herbal formulation (Jian Pi Yi Shen) stimulates HIF-2α and EPO protein expression in both the kidney and liver of rats with chronic kidney disease [20]. A novel HIF prolyl hydroxylase inhibitor (TP0463518) was found to induce dose-dependent EPO production from the liver in healthy volunteers and in patients with chronic kidney disease [21].…”

A Chinese Medicine Compound Alleviates Cisplatin-Induced Acute Kidney Injury via Its Antiapoptosis and Anti-Inflammation Effects in Mice

“…In particular, Jianpi Yishen Tang (JPYST) is a traditional Chinese medicine compound commonly used to treat chronic kidney diseases along with its complications [ 16 – 21 ]. In our previous studies, it was observed that JPYST protects 5/6 nephrectomized rat kidney from damage via suppression of inflammatory responses by inhibiting the NF- κ B activation and mediating downregulation of proinflammatory mediators in vitro [ 20 , 21 ].…”