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

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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Faculty Opinions recommendation of Renoprotective role of the vitamin D receptor in diabetic nephropathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1097755.553873 ◽

2008 ◽

Author(s):

Craig Langman

Keyword(s):

Vitamin D ◽

Diabetic Nephropathy ◽

Vitamin D Receptor

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The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection

Journal of Parasitology Research ◽

10.1155/2012/134645 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 18

Author(s):

James P. Whitcomb ◽

Mary DeAgostino ◽

Mark Ballentine ◽

Jun Fu ◽

Martin Tenniswood ◽

...

Keyword(s):

Vitamin D ◽

Immune Responses ◽

Vitamin D Receptor ◽

Leishmania Major ◽

Active Form ◽

Wild Type ◽

Vitamin D Signaling ◽

Deficient Mice ◽

Th 1

Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreasedLeishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance toL. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance toL. majorinfection but only in a host that is predisposed for Th-1 immune responses.

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Renoprotective role of the vitamin D receptor in diabetic nephropathy

Kidney International ◽

10.1038/sj.ki.5002572 ◽

2008 ◽

Vol 73 (2) ◽

pp. 163-171 ◽

Cited By ~ 199

Author(s):

Z. Zhang ◽

L. Sun ◽

Y. Wang ◽

G. Ning ◽

A.W. Minto ◽

...

Keyword(s):

Vitamin D ◽

Diabetic Nephropathy ◽

Vitamin D Receptor

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The role of vitamin D in autoimmune diseases: could sex make the difference?

Biology of Sex Differences ◽

10.1186/s13293-021-00358-3 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Maria Luisa Dupuis ◽

Maria Teresa Pagano ◽

Marina Pierdominici ◽

Elena Ortona

Keyword(s):

Vitamin D ◽

Autoimmune Diseases ◽

Vitamin D Receptor ◽

Immune Modulation ◽

Current Knowledge ◽

Active Form ◽

Adaptive Immune System ◽

Sex And Gender ◽

Mediated Effects

AbstractOver the last decades, a central role for vitamin D in immune modulation has been well established. The active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the interaction with vitamin D receptor, exerts different activities on the innate and adaptive immune system, among which suppression of inflammation and promotion of tolerogenic responses. Vitamin D insufficiency has been linked to autoimmune disorders that commonly display significant differences between females and males due to genetic, epigenetic, hormonal, and environmental factors. Notably, a number of studies recently showed a cross-talk between vitamin D and the sex hormone estrogen. Estrogen-mediated effects on immune response may favor a Th1 profile or a Th2 profile, depending on hormone concentration. Thus, estrogen-mediated effects appear to be variable on autoimmunity depending on its concentration but also on the pathogenic mechanisms underlying the different autoimmune diseases (i.e., Th1- or Th2-mediated diseases). Notably, estrogen has been demonstrated to enhance vitamin D function favoring its accumulation, and increasing the expression of vitamin D receptor, thus resulting in a more potent anti-inflammatory response in females than males. On the other hand, vitamin D has been shown to downregulate in immune cells the expression of aromatase, which converts testosterone to estrogen, leading to a decrease in estrogen level. Overall, available data allow us to hypothesize a higher protective effect of vitamin D-based therapeutic approaches in women, at least in fertile age, than in men. Future studies are needed to expand current knowledge on the immunomodulatory role of vitamin D in a sex and gender perspective, paving the way to a more personalized therapeutic approach in autoimmune diseases.

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Stimulation of the Proliferation of Mouse and Human Definitive Erythroid Progenitors By Activation of the Vitamin D Receptor Transcription Factor

Blood ◽

10.1182/blood-2018-99-113846 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1029-1029

Author(s):

Margaret H. Baron ◽

Jeffrey H. Barminko ◽

Brad M. Reinholt ◽

Mohandas Narla

Keyword(s):

Vitamin D ◽

Transcription Factor ◽

Signaling Pathway ◽

Vitamin D Receptor ◽

Vitamin D3 ◽

Fetal Liver ◽

Nuclear Hormone Receptor ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Stimulation Of

Abstract How the proliferation of erythroid progenitors is regulated is still now well understood. We found, using a computational analysis, that the vitamin D receptor(Vdr) nuclear hormone receptor transcription factor gene is expressed in the fetal and adult (definitive) but not the embryonic (primitive) stage of mouse erythroid ontogeny. Vdr is transcribed in definitive erythroid (EryD) progenitors and was downregulated during their maturation. VDR transcription factor activation by its ligand vitamin D3 (1,25(OH)2D3) results in conformational changes that stabilize the protein and induce its translocation into the nucleus, where it recruits co-regulatory complexes. The VDR signaling pathway has been studied primarily in the biology of bone but has been largely unexplored in erythropoiesis, where the limited published studies were performed almost exclusively in leukemic cell lines and not in normal primary cells. Activation of Vdr signaling by the vitamin D3 agonist calcitriol increased the outgrowth of EryD colonies from fetal liver and adult bone marrow, maintained progenitor potential, and delayed terminal erythroid maturation, as revealed by clonogenic assays, suspension culture studies, cell surface phenotype, and gene expression analyses. The stimulation in growth of erythroid progenitors resulted in a large increase in the numbers of mature red blood cells. The early (cKit+CD71lo/neg) but not the late (cKit+CD71hi) EryD progenitor subset of Linneg cKit+ cells was responsive both to calcitriol and to calcipotriol (which is 1-to-200 fold less potent in its calcemic effects than calcitriol). Therefore, the increase in progenitor numbers in response to calcitriol is mediated through activation of VDR rather than by effects on calcium flux. In preliminary studies of human Lineageneg cells, we find that the vitamin D agonists calcitriol and calcipotriol increase the numbers of CFU-E colony numbers from peripheral blood or BM. These results are similar to our findings for mouse. The glucocorticoid receptor (Gr), like Vdr, is a member of the nuclear hormone receptor transcription factor family and has been shown to stimulate the proliferation of cKit+CD71lo/neg cells. To determine whether the Vdr and Gr signaling pathways can cooperate to modulate erythroid progenitor growth, cKit+CD71lo/negcells were cultured with or without calcitriol, dexamethasone, or the two ligands in combination. Culture of cKit+CD71lo/neg progenitors in the presence of both calcitriol and dexamethasone resulted in an increase in proliferation that was at least additive, compared to either ligand alone, suggesting a role in stress erythropoiesis. This possibility is supported by our recent finding that an erythroid specific deletion in Vdr that interferes with DNA binding results in a reticulocytosis that occurs earlier and is more pronounced than in control animals, in response to phenylhydrazine (PHZ)-induced anemia. In addition, this deletion in Vdr blocked the increase in early erythroid progenitors from fetal liver seen for wild type mice. Lentivirus shRNA-mediated knockdown of Vdr expression abrogated the stimulation of early erythroid progenitor growth by calcitriol. These findings suggest that Vdr has a cell-intrinsic function in early erythroid progenitors. Activation of Vdr by calcitriol blocked the up regulation of the erythroid transcription factor genes Gata1, Fog1 and Klf1. In contrast, expression of genes known to regulate erythroid progenitors (Gata2, Zfp36l2, Bmi1, and Hopx) was not affected by Vdr signaling. Therefore, other genes must be involved in the Vdr signaling pathway in erythroid progenitors. Targeting of downstream components of the VDR signaling pathway could lead to new approaches for expansion of erythroid progenitors ex vivo. (This work was supported by grants to MHB from the NIH, R01 DK102945 and HL62248.) Disclosures No relevant conflicts of interest to declare.

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Role of endocannabinoid CB1 receptors in Streptozotocin-induced uninephrectomised Wistar rats in diabetic nephropathy

Beni-Suef University Journal of Basic and Applied Sciences ◽

10.1186/s43088-021-00121-y ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Jayarami Reddy Medapati ◽

Deepthi Rapaka ◽

Veera Raghavulu Bitra ◽

Santhosh Kumar Ranajit ◽

Girija Sankar Guntuku ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Morphological Changes ◽

Serum Levels ◽

Cb1 Receptors ◽

Protective Effects ◽

Renal Hypertrophy ◽

Necrosis Factor Alpha

Abstract Background The endocannabinoid CB1 receptor is known to have protective effects in kidney disease. The aim of the present study is to evaluate the potential agonistic and antagonistic actions and to determine the renoprotective potential of CB1 receptors in diabetic nephropathy. The present work investigates the possible role of CB1 receptors in the pathogenesis of diabetes-induced nephropathy. Streptozotocin (STZ) (55 mg/kg, i.p., once) is administered to uninephrectomised rats for induction of experimental diabetes mellitus. The CB1 agonist (oleamide) and CB1 antagonist (AM6545) treatment were initiated in diabetic rats after 1 week of STZ administration and were given for 24 weeks. Results The progress in diabetic nephropathy is estimated biochemically by measuring serum creatinine (1.28±0.03) (p < 0.005), blood urea nitrogen (67.6± 2.10) (p < 0.001), urinary microprotein (74.62± 3.47) (p < 0.005) and urinary albuminuria (28.31±1.17) (p < 0.0001). Renal inflammation was assessed by estimating serum levels of tumor necrosis factor alpha (75.69±1.51) (p < 0.001) and transforming growth factor beta (8.73±0.31) (p < 0.001). Renal morphological changes were assessed by estimating renal hypertrophy (7.38± 0.26) (p < 0.005) and renal collagen content (10.42± 0.48) (p < 0.001). Conclusions From the above findings, it can be said that diabetes-induced nephropathy may be associated with overexpression of CB1 receptors and blockade of CB1 receptors might be beneficial in ameliorating the diabetes-induced nephropathy. Graphical abstract

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Role of genetic variants of Vitamin D receptor, Toll-like receptor 2 and Toll-like receptor 4 in extrapulmonary tuberculosis

Microbial Pathogenesis ◽

10.1016/j.micpath.2021.104911 ◽

2021 ◽

pp. 104911

Author(s):

Bilal Ahmad Wani ◽

Faheem Shehjar ◽

Sonaullah Shah ◽

Ajaz Koul ◽

Adfar Yusuf ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Genetic Variants ◽

Extrapulmonary Tuberculosis ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Toll Like Receptor 2

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Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

Endocrine Reviews ◽

10.1210/er.2016-1070 ◽

2016 ◽

Vol 37 (5) ◽

pp. 521-547 ◽

Cited By ~ 97

Author(s):

Peter J. Tebben ◽

Ravinder J. Singh ◽

Rajiv Kumar

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Active Form ◽

Elevated Serum ◽

Diagnosis And Treatment ◽

Vitamin D Metabolites ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Stone Formers ◽

25 Hydroxyvitamin D

AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

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