The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice

Author:

Dahan Inbal1,Thawho Nadia1,Farber Evgeny2,Nakhoul Nakhoul3,Asleh Rabea4,Levy Andrew P.4ORCID,Li Yan Chun5,Ben-Izhak Ofer67,Nakhoul Farid123ORCID

Affiliation:

1. Diabetes and Metabolism Lab, The Baruch Padeh Medical Center, Poriya, Lower Galilee, Israel

2. Nephrology and Hypertension Division, The Baruch Padeh Medical Center, Poriya, Lower Galilee, Israel

3. The Azrieli Faculty of Medicine in Zfat in the Galilee, Bar-Ilan University, Ramat-Gan, Israel

4. The Vascular Medicine Lab, Technion, Faculty of Medicine, Rappaport Institute, Haifa, Israel

5. Department of Medicine, The University of Chicago, Chicago, IL 60637, USA

6. Department of Pathology, Rambam Health Care Campus, Haifa, Israel

7. Technion, Haifa, Israel

Abstract

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 theα-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 theα-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 decreasedα-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.

Funder

Israel Science Foundation

Publisher

Hindawi Limited

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3