The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice
The haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the...
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Wiley
2018-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2018/7163652 |
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| author | Inbal Dahan Nadia Thawho Evgeny Farber Nakhoul Nakhoul Rabea Asleh Andrew P. Levy Yan Chun Li Ofer Ben-Izhak Farid Nakhoul |
| author_facet | Inbal Dahan Nadia Thawho Evgeny Farber Nakhoul Nakhoul Rabea Asleh Andrew P. Levy Yan Chun Li Ofer Ben-Izhak Farid Nakhoul |
| author_sort | Inbal Dahan |
| collection | DOAJ |
| description | The haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the precise mechanism of the PCT injury in diabetic nephropathy (DN) remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of the α-klotho protein. In this study, we set out to test the hypothesis that the increased renal iron deposits in the PCT of Hp 2-2 DN affect the α-klotho-vitamin D receptor (VDR) axis and thereby exacerbates the PCT injury generated by the iron deposits. Immunohistochemical analysis of human and mouse kidney biopsies along with western blot analysis showed that the increased iron deposits in the PCT of the Hp 2-2 genotype were accompanied with significantly decreased α-klotho and VDR renal expression but significantly increased 1-α-hydroxylase renal expression. In conclusion, the iron-klotho-VDR axis is a major player in the mechanism contributing to iron-mediated PCT injury in diabetic Hp 2-2 mice and patients. Targeting this axis may open the way for new ideas regarding the pathogenesis and treatment of DN. |
| format | Article |
| id | doaj-art-ffe5171d20eb43d5887ba30679e73b64 |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-ffe5171d20eb43d5887ba30679e73b642025-02-03T01:10:00ZengWileyJournal of Diabetes Research2314-67452314-67532018-01-01201810.1155/2018/71636527163652The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and MiceInbal Dahan0Nadia Thawho1Evgeny Farber2Nakhoul Nakhoul3Rabea Asleh4Andrew P. Levy5Yan Chun Li6Ofer Ben-Izhak7Farid Nakhoul8Diabetes and Metabolism Lab, The Baruch Padeh Medical Center, Poriya, Lower Galilee, IsraelDiabetes and Metabolism Lab, The Baruch Padeh Medical Center, Poriya, Lower Galilee, IsraelNephrology and Hypertension Division, The Baruch Padeh Medical Center, Poriya, Lower Galilee, IsraelThe Azrieli Faculty of Medicine in Zfat in the Galilee, Bar-Ilan University, Ramat-Gan, IsraelThe Vascular Medicine Lab, Technion, Faculty of Medicine, Rappaport Institute, Haifa, IsraelThe Vascular Medicine Lab, Technion, Faculty of Medicine, Rappaport Institute, Haifa, IsraelDepartment of Medicine, The University of Chicago, Chicago, IL 60637, USADepartment of Pathology, Rambam Health Care Campus, Haifa, IsraelDiabetes and Metabolism Lab, The Baruch Padeh Medical Center, Poriya, Lower Galilee, IsraelThe haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the precise mechanism of the PCT injury in diabetic nephropathy (DN) remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of the α-klotho protein. In this study, we set out to test the hypothesis that the increased renal iron deposits in the PCT of Hp 2-2 DN affect the α-klotho-vitamin D receptor (VDR) axis and thereby exacerbates the PCT injury generated by the iron deposits. Immunohistochemical analysis of human and mouse kidney biopsies along with western blot analysis showed that the increased iron deposits in the PCT of the Hp 2-2 genotype were accompanied with significantly decreased α-klotho and VDR renal expression but significantly increased 1-α-hydroxylase renal expression. In conclusion, the iron-klotho-VDR axis is a major player in the mechanism contributing to iron-mediated PCT injury in diabetic Hp 2-2 mice and patients. Targeting this axis may open the way for new ideas regarding the pathogenesis and treatment of DN.http://dx.doi.org/10.1155/2018/7163652 |
| spellingShingle | Inbal Dahan Nadia Thawho Evgeny Farber Nakhoul Nakhoul Rabea Asleh Andrew P. Levy Yan Chun Li Ofer Ben-Izhak Farid Nakhoul The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice Journal of Diabetes Research |
| title | The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice |
| title_full | The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice |
| title_fullStr | The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice |
| title_full_unstemmed | The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice |
| title_short | The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice |
| title_sort | iron klotho vdr axis is a major determinant of proximal convoluted tubule injury in haptoglobin 2 2 genotype diabetic nephropathy patients and mice |
| url | http://dx.doi.org/10.1155/2018/7163652 |
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