Academic Journal
Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice
| العنوان: | Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice |
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| المؤلفون: | Sugahara, Mai, Tanaka, Shinji, Tanaka, Tetsuhiro, Saito, Hisako, Ishimoto, Yu, Wakashima, Takeshi, Ueda, Masatoshi, Fukui, Kenji, Shimizu, Akira, Inagi, Reiko, Yamauchi, Toshimasa, Kadowaki, Takashi, Nangaku, Masaomi |
| المساهمون: | Japan Society for the Promotion of Science, Japan Tobacco Inc |
| المصدر: | Journal of the American Society of Nephrology ; volume 31, issue 3, page 560-577 ; ISSN 1046-6673 1533-3450 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health) |
| سنة النشر: | 2020 |
| الوصف: | Significance Statement Prolyl hydroxylase domain (PHD) inhibitors, primarily developed to treat renal anemia, stimulate erythropoietin production through activation of hypoxia-inducible factor (HIF). Because HIF affects a broad spectrum of genes, PHD inhibitors are thought likely to have other effects, including protection against metabolic disorders. The authors show that in obese type 2 diabetic mice, administration of the PHD inhibitor enarodustat not only improves glucose and lipid metabolism, but also reduces albuminuria and ameliorates glomerular epithelial and endothelial damage. Enarodustat-treated mice also exhibit reduced glomerular expression and urinary excretion of C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1). The authors further demonstrate that enarodustat directly suppresses CCL2/MCP-1 production via HIF-1 activation in mesangial cells. These results indicate that enarodustat has renoprotective effects in addition to its potential to protect against metabolic disorders. Background Prolyl hydroxylase domain (PHD) inhibitors, which stimulate erythropoietin production through the activation of hypoxia-inducible factor (HIF), are novel therapeutic agents used for treating renal anemia. Several PHD inhibitors, including enarodustat, are currently undergoing phase 2 or phase 3 clinical trials. Because HIF regulates a broad spectrum of genes, PHD inhibitors are expected to have other effects in addition to erythropoiesis, such as protection against metabolic disorders. However, whether such beneficial effects would extend to metabolic disorder–related kidney disease is largely unknown. Methods We administered enarodustat or vehicle without enarodustat in feed to diabetic black and tan brachyury (BTBR) ob/ob mice from 4 to 22 weeks of age. To elucidate molecular changes induced by enarodustat, we performed transcriptome analysis of isolated glomeruli and in vitro experiments using murine mesangial cells. Results Compared with BTBR ob/ob mice that received only vehicle, ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1681/asn.2019060582 |
| DOI: | 10.1681/ASN.2019060582 |
| الاتاحة: | http://dx.doi.org/10.1681/asn.2019060582 https://journals.lww.com/10.1681/ASN.2019060582 |
| رقم الانضمام: | edsbas.7F865BBE |
| قاعدة البيانات: | BASE |
| DOI: | 10.1681/asn.2019060582 |
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