Collagen Hydrolysate Corrects Anemia in Chronic Kidney Disease via Anti-Inflammatory Renoprotection and HIF-2α-Dependent Erythropoietin and Hepcidin Regulation

Abstract

Anemia is a common chronic kidney disease (CKD) complication contributing to increased morbidity and mortality. Collagen-based traditional Chinese nutraceuticals have long been used in antianemic therapies. This study aims to investigate the therapeutic effectiveness of porcine collagen hydrolysate (CH) and its underlying mechanism in the treatment of renal anemia by using adenine-induced CKD mice, RAW264.7 macrophages, and HepG2 hepatoma cells, with prolyl-hydroxyproline as a reference compound for collagen-derived hydroxyproline-containing di-/tripeptides. CH was found to alleviate renal filtering dysfunction, systemic and kidney inflammation, liver hepcidin overproduction and anemia and to increase erythropoietin production and hypoxia inducible factor (HIF)-2α stability in liver and kidney in CKD mice. Prolyl-hydroxyproline exerted direct anti-inflammatory effects on lipopolysaccharide-activated macrophages and elicited stimulating and inhibiting activities on erythropoietin expression and hepcidin overproduction, respectively, in HepG2 cells by HIF-2α activation. Overall, CH was effective in correcting renal anemia via anti-inflammatory renoprotection and HIF-2α-dependent erythropoietin and hepcidin regulation.

Collagen Peptides as a Hypoxia-Inducible Factor-2α-Stabilizing Prolyl Hydroxylase Inhibitor to Stimulate Intestinal Iron Absorption by Upregulating Iron Transport Proteins

“…To validate whether collagen peptides could stimulate intestinal nonheme iron absorption in vivo, CH and Pro-Hyp were orally administered to female rats with the duodenal gene transcriptional levels of Dcytb, DMT1, FPN, and HEPH measured at 2 h post-dose, a time point chosen to exclude the possibility that their effects on duodenal gene expression were secondary to their regulation of systemic erythropoietin and hepcidin production according to previous studies. , As shown in Figure a,b, CH and Pro-Hyp induced significantly increased the duodenal gene transcription levels of Dcytb, DMT1, FPN, and HEPH in rats in a dose-dependent manner, confirming direct stimulation of intestinal nonheme iron absorption by collagen peptides in vivo. According to the western blotting results (Figure c,d), the CH and Pro-Hyp dose-dependently increased the duodenal protein level of HIF-2α in rats, validating the activation of HIF-2α signaling by collagen peptides in vivo.…”

“…17,18 Our recent studies revealed the HCP-dependent correction of anemia associated with iron deficiency and chronic kidney disease by dietary collagen via the HIF-2α-mediated regulation of erythropoietin and hepcidin production. 19,20 We hypothesize that HCPs may serve as PHD inhibitors to activate the HIF-2α signaling pathway. The present study observed the effects of collagen peptides to stimulate intestinal nonheme iron absorption by HIF-2α-dependent upregulation of Dcytb, DMT1, FPN, and HEPH in polarized Caco-2 cell monolayers and characterized the PHD inhibiting activity of HCPs by using recombinant human PHD3 protein and molecular docking analysis.…”

“…There are a wide range of collagen-based traditional Chinese medicines made from animal connective tissues (e.g., hides, bones, horns, and swim bladders), and they have been employed in nutraceutical therapies for anemia in China for over 2000 years. − Collagen-derived hydroxyproline-containing di-/tripeptides (HCPs) in human blood are beneficial to skin, bone, joint, and cardiovascular health by stimulating skin fibroblast growth, promoting hyaluronic acid production in fibroblasts, chondrocytes, and synovium cells, and inducing the differentiation of osteoblasts, preadipocytes, myoblasts, chondrocytes, and T-helper cells. , Our recent studies revealed the HCP-dependent correction of anemia associated with iron deficiency and chronic kidney disease by dietary collagen via the HIF-2α-mediated regulation of erythropoietin and hepcidin production. , We hypothesize that HCPs may serve as PHD inhibitors to activate the HIF-2α signaling pathway. The present study observed the effects of collagen peptides to stimulate intestinal nonheme iron absorption by HIF-2α-dependent upregulation of Dcytb, DMT1, FPN, and HEPH in polarized Caco-2 cell monolayers and characterized the PHD inhibiting activity of HCPs by using recombinant human PHD3 protein and molecular docking analysis.…”

A challenging diagnosis of rare co-existent multiple myeloma and prostate adenocarcinoma: a systematic review of case reports

“…These are the cytokines that may reduce the use of iron reserves from reticuloendothelial cells and may prevent the kidney from producing EPO. Additionally, they directly suppress the growth of erythroid precursor cells 28 .…”

Stabilizing Hypoxia-Inducible Factor to Manage Anemia in Chronic Kidney Disease: From Basic Theory to Clinical Study

“…In a study that interferes with PHD2 [ 24 ], the stability of HIF is upregulated, and the erythrocyte pressure ratio level and EPO of mice are both markedly elevated. In the progression of CKD to end-stage renal disease (ESRD), peritubular interstitial fibroblasts differentiate into myofibroblasts, and renal EPO production capacity turns down [ 25 ]. Nevertheless, failure of PHD protein is able to restore the expression of EPO gene in the impaired kidney.…”