Hypoxia-Inducible Factor-Prolyl Hydroxylase Domain Inhibitors to Treat Anemia in Chronic Kidney Disease

2019 ◽  
pp. 112-123 ◽  
Author(s):  
Midori Sakashita ◽  
Tetsuhiro Tanaka ◽  
Masaomi Nangaku
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Prolyl Hydroxylase Domain

scholarly journals SP334IRON REGULATION BY MOLIDUSTAT, BAY 85-3934, A DAILY ORAL HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITOR IN PATIENTS WITH CHRONIC KIDNEY DISEASE

2018 ◽  
Vol 33 (suppl_1) ◽  
pp. i457-i457 ◽  
Author(s):  
Tadao Akizawa ◽  
Iain C Macdougall ◽  
Jeffrey S Berns ◽  
Thomas Bernhardt ◽  
Megumi Taguchi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Prolyl Hydroxylase Inhibitor

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.

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