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

Dahan, Inbal; Thawho, Nadia; Farber, Evgeny; Nakhoul, Nakhoul; Asleh, Rabea; Levy, Andrew P.; Li, Yan Chun; Ben‐Izhak, Ofer; Nakhoul, Farid

doi:10.1155/2018/7163652

Cited by 12 publications

(8 citation statements)

References 46 publications

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“…As expected, the Hb clearance function of diabetic mice with genotype HP 2-2 is impaired. For instance, the increase in iron deposits and oxidative stress in the proximal convoluted tubules (PCT) leads to a decrease expression of α-klotho and VDR in renal tubules, accompanied with increasing PCT damage and worsening kidney injury, thereby increasing the incidence of DN and its complications among Hp 2-2 genotype patients [22]. Besides, other studies have demonstrated that microtubule-associated protein 1 light chain 3 (LC3), which acts as a VDR-binding protein for transporting to the nucleus, could inhibit HG-induced fibrotic gene expressions in HK-2 cells by promoting the VDR-RXR dimer formation [47].…”

Section: The Mechanism Of Vd/vdr In Renal Tubulementioning

confidence: 99%

“…According to many publications, VD/VDR is inextricably linked to the development of many diseases. Lots of studies have showed that VD/VDR plays a crucial role in the physiological and pathological processes of cancer [ 8 , 16 , 18 – 21 ], DN [ 3 , 22 , 23 ], autoimmune diseases, inflammation, infection, cardiovascular disease [ 1 , 24 ], hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) [ 2 ], etc. O. Teriolo et al have reported the role of VD/VDR in gynecological diseases, such as breast cancer, ovarian cancer, polycystic ovary syndrome, and endometriosis.…”

Section: Vitamin D and Vitamin D Receptormentioning

confidence: 99%

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The Emerging Role of Vitamin D and Vitamin D Receptor in Diabetic Nephropathy

Lei

Liu

Guo

2020

BioMed Research International

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Diabetic nephropathy (DN), one of the most common and severe microvascular complications of diabetes mellitus (DM), is an important risk factor for DM patient’s death. Nowadays, DN has become the leading cause of end-stage renal disease (ESRD) in most countries without effective therapeutic methods. Recently, the renoprotective effects mediated by vitamin D (VD) and vitamin D receptor (VDR) have been evidenced. VD, a kind of steroid with the active form 1,25(OH)2D3, has been known for the crucial roles in the modulation of serum calcium and phosphorus concentrations. It exerts important functions by binding with its receptor VDR.VDR, a transcription factor located at chromosome 12 containing 9 exons, is one of the nonsteroid nuclear hormone receptor superfamily, which participates in transcriptional regulation of genes in tissue- and cell-specific ways. Increasing evidences have demonstrated that VD/VDR signaling pathway possesses a variety of kidney-protective effects in DN patients, such as antiproteinuria, antifibrosis, anti-inflammatory, and preventing podocyte damage. Although there are many studies on the role of the VD/VDR signaling pathway in DN, the effects and mechanisms still need to be further explained. This review summarized the multiple roles of VD/VDR in podocyte injury, tubule lesions, interstitial fibrosis, and inflammation, as well as the clinical applications about DN to explore much more and effective therapeutic methods for DN.

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Section: The Mechanism Of Vd/vdr In Renal Tubulementioning

confidence: 99%

Section: Vitamin D and Vitamin D Receptormentioning

confidence: 99%

The Emerging Role of Vitamin D and Vitamin D Receptor in Diabetic Nephropathy

Lei

Liu

Guo

2020

BioMed Research International

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“…Excessive iron deposition in kidney cells can cause tissue dysfunction [ 4 ]. The abnormal accumulation of iron may promote the occurrence and development of diabetic nephropathy by increasing oxidative/nutritional stress and reducing antioxidant capacity [ 5 , 6 ]. The discovery of iron death provides a new explanation for the role of iron overload in the pathogenesis of the disease.…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches

Liu

et al. 2021

PLoS ONE

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Diabetic nephropathy is one of the common microvascular complications of diabetes. Iron death is a recently reported way of cell death. To explore the effects of iron death on diabetic nephropathy, iron death score of diabetic nephropathy was analyzed based on the network and pathway levels. Furthermore, markers related to iron death were screened. Using RNA-seq data of diabetic nephropathy, samples were clustered uniformly and the disease was classified. Differentially expressed gene analysis was conducted on the typed disease samples, and the WGCNA algorithm was used to obtain key modules. String database was used to perform protein interaction analysis on key module genes for the selection of Hub genes. Moreover, principal component analysis method was applied to get transcription factors and non-coding genes, which interact with the Hub gene. All samples can be divided into two categories and principal component analysis shows that the two categories are significantly different. Hub genes (FPR3, C3AR1, CD14, ITGB2, RAC2 and ITGAM) related to iron death in diabetic nephropathy were obtained through gene expression differential analysis between different subtypes. Non-coding genes that interact with Hub genes, including hsa-miR-572, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-208a-3p, hsa-miR-153-3p and hsa-miR-29c-3p, may be related to diabetic nephropathy. Transcription factors HIF1α, KLF4, KLF5, RUNX1, SP1, VDR and WT1 may be related to diabetic nephropathy. The above factors and Hub genes are collectively involved in the occurrence and development of diabetic nephropathy, which can be further studied in the future. Moreover, these factors and genes may be potential target for therapeutic drugs.

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“…Otto-Duessel [44] observed that the lack of VD in iron overload disease was related to the accumulation of liver iron. Excessive iron accumulation in the kidney would affect VDR, which would aggravate iron deposition and cause damage to the proximal tubules of the kidney [45] . In our study, the serum 25-(OH)D 3 and 1,25-(OH) 2 D 3 levels in the HFe group were not found to be inhibited.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Iron Dextran on Vitamin D3 Metabolism in SD Rats

Qiu

et al. 2021

Preprint

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Background: The status of iron and vitamin D (VD) is essential to health. Previous studies have shown that iron homeostasis has a potential effect on VD metabolism, but the mechanism is not fully understood. Objectives: To explore the relationship between VD metabolism and iron metabolism, as well as the regulatory mechanism of iron on VD metabolism. Methods: Methods: 40 male rats were fed adaptively for 7 days and randomly divided into control (C, n=6 normal diet) group and model (M, n=24 iron deficient diet) group according to body weight, the latter was used to establish iron deficiency anemia (IDA) model. After 6 weeks of feeding, the M group was randomly divided into: deficiency iron group (DFe), low iron group (LFe), medium iron group (MFe) and high iron group (HFe) according to the level of hemoglobin (Hb). Different doses of iron dextran (based on iron content (100g·bw·d)): 0, 1.1, 3.3 and 9.9mg were given respectively. After 4 weeks, the rats were anesthetized with 8% chloral hydrate, blood was collected from the abdominal aorta, liver and kidney tissues were collected. The serum and tissues were separately packed and frozen at -80℃ for testing. Results: The results showed that the levels of Hb, RBC, serum iron (SI), liver iron, and kidney iron DFe group were lower than those in the other four groups, while the levels of total iron-binding capacity (TIBC), transferrin (TF) and transferrin receptor (Tfr) in DFe group were higher than those in other groups; The serum levels of 25-(OH)D3 and 1,25-(OH)2D3 in DFe group were significantly lower than those in C group (P < 0.05). The correlation analysis showed that the levels of 25-(OH)D3 and 1,25-(OH)2D3 were negatively correlated with TIBC, TF and Tfr no correlation with SI. Western blot, immunofluorescence, and q-PCR results showed that compared with C group, the protein and gene expressions of CYP2R1, CYP27A1, and CYP24A1 in DFe group were down-regulated, and the expression of CYP27B1 protein and gene was up-regulated in DFe group. Conclusion: Therefore, iron may be involved in the metabolism of VD3 by regulating the expression of VD3 hydroxylase, suggesting that appropriate iron supplementation can promote the activation of VD3.

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

Cited by 12 publications

References 46 publications

The Emerging Role of Vitamin D and Vitamin D Receptor in Diabetic Nephropathy

The Emerging Role of Vitamin D and Vitamin D Receptor in Diabetic Nephropathy

Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches

The Effect of Iron Dextran on Vitamin D3 Metabolism in SD Rats

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