MO544EFFECT OF DIFFERENT FREQUENCY OF FG-4592 ON CHRONIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Di Yin ◽  
Zuolin Li ◽  
Zhao-ying Ding ◽  
Bicheng Liu
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Renal Anemia ◽  
Vehicle Group ◽  
Intragastric Administration ◽  
Continuous Administration ◽  
Treatment Frequency ◽  
Intermittent Administration

Abstract Background and Aims Hypoxia inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is a novel small molecule inhibitor in clinical treatment for renal anemia. Several studies have shown that sustained HIF activation may also have deleterious effects, such as tubulointerstitial fibrosis. Here, the potential effects of different treatment frequency of HIF-PHI (FG-4592) on CKD (chronic kidney disease) mice were investigated. Method Male C57BL/6J mice were constructed by subtotal nephrectomy of 5/6 to serve as a model for CKD. We then compared four different strategies based on the frequency of FG-4592(intragastric administration, 30mg/kg) over 9 weeks: once a week (qw), twice a week (biw), three times a week (tiw), and every day (qd). In vitro, HK-2 cells were divided into three groups according to the different administration methods of FG-4592(30μM): FG-4592 for 20h (FG0); FG-4592 for 8h, followed by washing with medium for 12h(FG1); twice FG-4592 for 8h, followed by washing twice with medium for2h(FG2). Results Hemoglobin in the biw group, tiw group or qd group was significantly higher than that in vehicle group. EPO, HIF-1α and HIF-2α of tiw group, biw group and qd group were significantly higher than those in vehicle group. Makers of fibrosis and inflammation in qd group were higher than that in vehicle group, while there was no statistical difference in the changes of the above indicators in tiw group and biw group. HIF-1α and HIF-2α were increased in intermittent administration, but the expression of VEGF, makers of fibrosis or inflammation were not affected. In HK2, HIF-1α and HIF-2α were activated by continuous administration of FG-4592. At the same time, the expression of VEGF, inflammatory and fibrosis indicators were increased significantly during continuous administration. In HepG2, EPO was increased in intermittent administration in HepG2 cells without VEGF increasing. Conclusion Taken together, our studies demonstrated that FG-4592 administration 2-3 times a week can effectively improve renal anemia without side effects on inflammatory and fibrosis.

scholarly journals Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease

2019 ◽  
Vol 317 (5) ◽  
pp. F1265-F1273 ◽  
Author(s):  
Fang-Yuan Qian ◽  
Zuo-Lin Li ◽  
Yu-Dong Guo ◽  
Han-Chao Gao ◽  
Li-Hua Gu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Vehicle Group ◽  
Acute Ischemia ◽  
High Dose ◽  
Dependent Manner ◽  
Prolyl Hydroxylase Inhibitor

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

scholarly journals Hypoxia inducible factor stabilizers: a promising treatment for chronic kidney disease

2020 ◽  
Vol 9 (11) ◽  
pp. 1766
Author(s):  
Koushiki Mani ◽  
Johnny Karini ◽  
Kuntolika Mani ◽  
Ananya Amrit
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Supplementation ◽  
Hypoxia Inducible Factor ◽  
Renal Anemia ◽  
Erythropoietin Production ◽  
Cell Life ◽  
Oxygen Sensitive ◽  
Promising Treatment ◽  
Hif Pathway

Anemia in chronic kidney disease (CKD) is a very common complication. The two main factors contributing to the development of anemia in CKD is decreased erythropoietin production and iron deficiency. Other factors that might play a role in the pathogenesis of renal anemia are: chronic inflammation leading to increased hepcidin, uremic toxins, and shorter red blood cell life span. The mainstay of treatment is iron supplementation, blood transfusion and erythropoietin stimulating agents (ESA). The discovery of hypoxia inducible factor (HIF) pathway has opened a new chapter in the treatment of anemia in CKD. The oxygen-sensitive HIF pathway plays a prominent role in the control of erythropoiesis and iron metabolism. HIF stabilizers are a new set of drugs that inhibits prolyl hydroxylase domain (PHD) proteins which are key regulators of HIF activity. Several such compounds are being developed to revolutionize the treatment of renal anemia.

scholarly journals Soluble Fas affects erythropoiesis in vitro and acts as a potential predictor of erythropoiesis-stimulating agent therapy in patients with chronic kidney disease

2020 ◽  
Vol 318 (4) ◽  
pp. F861-F869
Author(s):  
Daniela Mendes Chiloff ◽  
Danilo Candido de Almeida ◽  
Maria A. Dalboni ◽  
Maria Eugênia Canziani ◽  
Sunil K. George ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Dependent Manner ◽  
Potential Predictor ◽  
Soluble Fas ◽  
Esa Therapy

Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels ( r = 0.30, P = 0.001) but negatively with hemoglobin ( r = −0.55, P < 0.001) and glomerular filtration rate ( r = −0.58, P < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, P < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, P = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, P < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration ( r = −0.72, P < 0.001). There was decreased erythroid colony formation in vitro when CD34+ HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, P < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.

Nutritional compounds influence tissue factor expression and inflammation of chronic kidney disease patients in vitro

Nutrition ◽  
2011 ◽  
Vol 27 (9) ◽  
pp. 967-972 ◽  
Author(s):  
Cecilia M. Shing ◽  
Murray J. Adams ◽  
Robert G. Fassett ◽  
Jeff S. Coombes
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Tissue Factor ◽  
Tissue Factor Expression ◽  
Factor Expression ◽  
Nutritional Compounds

scholarly journals Paracrine Proangiogenic Function of Human Bone Marrow-Derived Mesenchymal Stem Cells Is Not Affected by Chronic Kidney Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Femke C. C. van Rhijn-Brouwer ◽  
Bas W. M. van Balkom ◽  
Diana A. Papazova ◽  
Diënty H. M. Hazenbrink ◽  
Anke J. Meijer ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Bone Marrow ◽  
Kidney Disease ◽  
Kidney Transplant ◽  
Galactosidase Activity ◽  
Kidney Transplant Recipients ◽  
Paracrine Factors ◽  
Differentiation Capacity ◽  
Scratch Wound

Background. Cell-based therapies are being developed to meet the need for curative therapy in chronic kidney disease (CKD). Bone marrow- (BM-) derived mesenchymal stromal cells (MSCs) enhance tissue repair and induce neoangiogenesis through paracrine action of secreted proteins and extracellular vesicles (EVs). Administration of allogeneic BM MSCs is less desirable in a patient population likely to require a kidney transplant, but potency of autologous MSCs should be confirmed, given previous indications that CKD-induced dysfunction is present. While the immunomodulatory capacity of CKD BM MSCs has been established, it is unknown whether CKD affects wound healing and angiogenic potential of MSC-derived CM and EVs. Methods. MSCs were cultured from BM obtained from kidney transplant recipients (N=15) or kidney donors (N=17). Passage 3 BM MSCs and BM MSC-conditioned medium (CM) were used for experiments. EVs were isolated from CM by differential ultracentrifugation. BM MSC differentiation capacity, proliferation, and senescence-associated β-galactosidase activity was assessed. In vitro promigratory and proangiogenic capacity of BM MSC-derived CM and EVs was assessed using an in vitro scratch wound assay and Matrigel angiogenesis assay. Results. Healthy and CKD BM MSCs exhibited similar differentiation capacity, proliferation, and senescence-associated β-galactosidase activity. Scratch wound migration was not significantly different between healthy and CKD MSCs (P=0.18). Healthy and CKD BM MSC-derived CM induced similar tubule formation (P=0.21). There was also no difference in paracrine regenerative function of EVs (scratch wound: P=0.6; tubulogenesis: P=0.46). Conclusions. Our results indicate that MSCs have an intrinsic capacity to produce proangiogenic paracrine factors, including EVs, which is not affected by donor health status regarding CKD. This suggests that autologous MSC-based therapy is a viable option in CKD.

scholarly journals Platelets of patients with chronic kidney disease demonstrate deficient platelet reactivity in vitro

2012 ◽  
Vol 13 (1) ◽  
Author(s):  
Esther R van Bladel ◽  
Rosa L de Jager ◽  
Daisy Walter ◽  
Loes Cornelissen ◽  
Carlo A Gaillard ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Platelet Reactivity
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