دورية أكاديمية
Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a "U-shaped" relationship.
العنوان: | Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a "U-shaped" relationship. |
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المؤلفون: | Shi M; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas., Flores B; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas., Li P; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas.; Department of Nephrology, Yu-Huang-Ding Hospital, Qingdao University , Yantai, Shandong , People's Republic of China., Gillings N; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas., McMillan KL; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas., Ye J; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas., Huang LJ; Department of Cell Biology, University of Texas Southwestern Medical Center , Dallas, Texas., Sidhu SS; Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto , Toronto, Ontario , Canada., Zhong YP; Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University , Portland, Oregon., Grompe MT; Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University , Portland, Oregon., Streeter PR; Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University , Portland, Oregon., Moe OW; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas.; Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas.; Department of Physiology, University of Texas Southwestern Medical Center , Dallas, Texas., Hu MC; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas.; Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas. |
المصدر: | American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2018 Apr 01; Vol. 314 (4), pp. F501-F516. Date of Electronic Publication: 2017 Nov 29. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901990 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1466 (Electronic) Linking ISSN: 15221466 NLM ISO Abbreviation: Am J Physiol Renal Physiol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Bethesda, Md. : American Physiological Society, c1997- |
مواضيع طبية MeSH: | Neovascularization, Physiologic*, Acute Kidney Injury/*metabolism , Capillaries/*metabolism , Erythropoietin/*metabolism , Kidney Tubules, Proximal/*blood supply , Kidney Tubules, Proximal/*metabolism , Receptors, Erythropoietin/*metabolism, Acute Kidney Injury/genetics ; Acute Kidney Injury/pathology ; Acute Kidney Injury/physiopathology ; Animals ; Apoptosis ; Autophagy ; Capillaries/pathology ; Capillaries/physiopathology ; Cell Hypoxia ; Cells, Cultured ; Disease Models, Animal ; Fibrosis ; Humans ; Kidney Tubules, Proximal/pathology ; Kidney Tubules, Proximal/physiopathology ; Mice, 129 Strain ; Mice, Transgenic ; Receptors, Erythropoietin/deficiency ; Receptors, Erythropoietin/genetics ; Signal Transduction |
مستخلص: | The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a "U-shaped" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery. |
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معلومات مُعتمدة: | R01 DK091392 United States DK NIDDK NIH HHS; R01 DK092461 United States DK NIDDK NIH HHS; R01 HL089966 United States HL NHLBI NIH HHS; U01 HL110964 United States HL NHLBI NIH HHS |
فهرسة مساهمة: | Keywords: AKI; EpoR; autophagy; peritubular capillary; tubulointerstitial fibrosis |
المشرفين على المادة: | 0 (Epo protein, mouse) 0 (Receptors, Erythropoietin) 11096-26-7 (Erythropoietin) |
تواريخ الأحداث: | Date Created: 20171201 Date Completed: 20190422 Latest Revision: 20191008 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC5966758 |
DOI: | 10.1152/ajprenal.00306.2017 |
PMID: | 29187371 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1522-1466 |
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DOI: | 10.1152/ajprenal.00306.2017 |