The vitamin D receptor (VDR), first cloned in 19871 is a member of the nuclear receptors super family.2 After binding to its ligands, VDR activates or suppresses expression of its target genes by binding to their regulatory regions. Thus, VDR responds to changes in the metabolic environment. The most well-known function of the vitamin D endocrine system is maintaining calcium and phosphorus homoeostasis. However, studies in the past decades have revealed a wide range of activities for vitamin D other than the regulation of calcium and phosphorus metabolism. VDR is highly expressed in the kidney, and consistently, the kidney is considered as a major vitamin D target organ. VDR-activating agonists have renal protective effects in the context of diabetic nephropathy (DN). This review will discuss the roles of VDR in the pathogenesis and therapy of DN.
Biological characteristics of VDR
Vitamin D3 is either acquired from dietary sources or generated via solar ultraviolet irradiation of 7-dehydrocholesterol in the skin. Vitamin D3 is then processed into the active hormone, 1,25 dihydroxy vitamin D3 (1,25(OH)2-D3), via two consecutive hydroxylation reactions.3,4 The first such reaction takes place in the liver and is catalyzed by 25-hydroxylase. The second is catalyzed by 1α-hydroxylase, which is expressed predominantly in the kidney. The activity of 1,25(OH)2-D3 is mediated by VDR. 1,25(OH)2-D3-VDR has multiple physiological and pathological roles that extend beyond the regulation of mineral metabolism, including the regulation of renal and cardiovascular functions.5
To date, VDR cDNAs have been cloned from six species (i.e., human, rat, mouse, chicken, Japanese quail, and frog (Xenopus laevis)).6 All of these VDRs share significant sequence similarities. The human VDR gene localizes in chromosome 12q13-14.7 VDR has the typical nuclear receptors structure consisting of a DNA-binding domain (DBD) and a ligand-binding domain (LBD).
VDR was originally named on the basis of the observation that 1,25(OH)2-D3 is a ligand for this receptor. VDR's transcription depends on 1,25(OH)2-D3. In subsequent years, naturally occurring, low-affinity VDR ligands have been identified (for example, lithocholic acid, curcumin, and polyunsaturated fatty acids) and may trigger 1,25(OH)2-D3-independent activation.8 VDR forms a heterodimer with retinoid X receptors (RXRs) to modulate expression of target genes. The FXR-RXR heterodimer can also respond to ligands for RXR, such as the natural 9-cis retinoic acid (9-cis RA) hormone. VDR-RXR binds to vitamin D-responsive element (VDRE) in target genes, consisting of a direct repeat spaced by three nucleotides.9
VDRs are expressed in different types of cells including vascular smooth muscle cells, lymphocytes, osteoblasts, and cardiac myocytes.10,11 VDR is highly expressed in the kidney. Immunohistochemical studies indicate that VDR is expressed in proximal and distal tubular epithelial cells, glomerular parietal epithelial cells, and collecting duct cells. VDR is also found in the macula densa of the juxtaglomerular apparatus, glomerular parietal epithelial cells, and podocytes. In contrast, VDR is either very low or absent in interstitial fibroblasts, glomerular mesangial cells, and juxtaglomerular cells.12-15 The fact that VDR highly expresses in kidney highlights the importance of investigating the effects of VDR in not only wild-type mice but also VDR-deficient mice to determine the specificity of the effects. Indeed, VDR-deficient mice have greatly aided in studying the role of VDR in metabolism. The VDR knockout (VDRKO) mice are more susceptible to streptozotocin (STZ)-induced diabetic kidney disease. Under diabetic condition or unilateral ureteral obstruction, deficiency of VDR leads to severe renal injury largely owing to increased activation of local RAS in the kidney, resulting in early onset of robust albuminuria, glomerulosclerosis and interstitial fibrosis.16
Renoprotective role of VDR in DN
DN is the most common renal complication of diabetes mellitus and a leading cause of end-stage renal disease (ESRD). DN's initial feature is glomerular and tubuloepithelial hypertrophy and thickening of glomerular and tubular basement membrane followed by development of hyperfiltration and microalbuminuria that will progress to proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis and eventually lead to ESRD.17 The pathogenesis of DN is multifactorial and complex. Hypertension, abnormal carbohydrate metabolism, abnormal lipid metabolism, upregulation of profibrotic growth factors (including, renin, angiotensin II, and transforming growth factor β (TGF-β), upregulation of proinflammatory cytokines (including, nuclear factor kappa B (NF-κB), increased oxidative stress and increased production of advanced glycation end products play important roles in the pathogenesis and progression of diabetic nephropathy.18-21
Renal injury still progresses in most of patients treated with tight glucose control, tight blood pressure control, tight lipid control and angiotensin II receptor blockade, indicating that additional treatment modalities that modulate the pathogenic pathways involved in DN are needed to slow the progression of renal failure in patients with diabetes. Accumulating evidence indicate that VDR plays essential roles, not only in the regulation of mineral metabolism but also in the development of DN.
Mechanisms underlying the protective role of VDR
VDR and the renin-angiotensin system (RAS)
RAS is a regulatory cascade with angiotensin (Ang) II as the central effector. Ang II is generated by two enzymatic cleavages: the first is the rate-limiting step, in which angiotensinogen (AGT) is cleaved to Ang I by renin, a protease produced predominantly by the juxtaglomerular apparatus in the nephron; then Ang I is converted to Ang II by the angiotensin-converting enzyme (ACE).22 Through binding to its G protein-coupled receptors, Ang II exerts multiple physiologic and pathologic functions in regulating electrolytes, volume, and blood pressure homeostasis.23 Clinical studies have demonstrated that treatments with ACE inhibitors (ACEIs) or Ang II type 1 (AT1) receptor blockers (ARBs) reduce the progression of proteinuria, glomerulosclerosis and tubulointerstitial fibrosis in diabetic patients, suggesting that the RAS is a major mediator of progressive renal injury in DN.24-27
Given the RAS's critical role in renal injury and the reninsuppressing effect of vitamin D, the expressions of renin, AGT and AT1 receptor in the kidney are higher in VDRKO mice than in WT mice under diabetic condition. Moreover, the expression of TGF-β, the downstream effectors of Ang II, is also increased more in diabetic VDRKO mice.22
A study by Zhang et al28 demonstrated that diabetic VDRKO mice developed more severe nephropathy than WT mice due to enhanced RAS activation in the kidney, confirming that VDR plays a protective role against hyperglycemia-induced renal injury by RAS suppression. This study used an STZ-induced type 1 diabetes model. Diabetes was induced in VDRKO mice and WT mice with low-dose STZ injection and the mice were monitored for 19 weeks. Diabetic WT and VDRKO mice developed the same degree of progressive hyperglycemia. However, VDRKO mice developed earlier and more severe albuminuria than WT mice. Consistent with the more severe albuminuric phenotype is the impairment of the glomerular filtration barrier in VDRKO mice revealed by electron microscopy, including a marked thickening of the glomerular basement membrane and an increase in podocyte foot process effacement. In null mutant mice lacking VDR renin expression was drastically upregulated in the kidney, leading to marked elevation of plasma renin and Ang II, which causes hypertension and cardiac hypertrophy.29-31 Targeted expression of human VDR in the juxtaglomerular cells in transgenic mice using the renin gene promoter led to suppression of renin expression and this inhibitory effect is independent of parathyroid hormone and calcium, suggesting a direct role of the receptor in the regulation of renin production.32
Levi et al33 showed that VDR agonist doxercalciferol (1α-hydroxyvitamin D2) prevents the activation of the rennin angiotensin aldosterone system including the angiotensin II type 1 receptor and the mineralocorticoid receptor in mice with diet-induced obesity (DIO) and insulin resistance. The treatment of DIO mice with the VDR agonist decreased proteinuria, podocyte injury, mesangial expansion, and extracellular matrix protein accumulation. Nephrin, a key component of the slit diaphragm of the glomerular filtration barrier, was significantly reduced in the kidney of VDRKO mice. Moreover, diabetic VDRKO mice also developed more severe glomerulosclerosis, suggested by semi-quantitative glomerulosclerotic index data. Consistently, extracellular matrix protein, such as fibronectin, was markedly increased in the glomerular mesangium of VDRKO mice.
VDR, inflammation and fibrosis
Inflammation is the universal initial response of an organism to any injurious agent. Effective inflammatory response leads to removal of the injurious factor and subsequently resolution of inflammation and initiation of tissue repair. Tissue repair is a highly complex process that includes epithelial cell production, angiogenesis and extra cellular matrix production.34 In mammals, because tissue regeneration is restricted, the repair process involves fibrosis. Excessive fibrosis leads to organ failure.35,36 Inflation and fibrosis are considered indispensable components of the same process of the body's response to injury.37
NF-κB regulates a wide range of genes involved in inflammation and fibrogenesis (such as tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1) that are involved in the development of kidney disease and play key roles in kidney disease development. Bacterial infection, lipoplysachride (LPS) and high glucose are known to activate NF-κB in kidney cells. NF-κB activation has been reported in patients with diabetic nephropathy.38 In a mouse model of unilateral urethral obstruction, monocytes and T cells infiltrate the interstitium of the obstructed kidney and produce TNF-α. TNF-α, through the transcription factor NF-κB, induces the production of RANTES (the regulated-upon activation, normal T-cell expressed and secreted) chemokine by renal tubular cells, which promotes further kidney infiltration by monocytes and T cells and closes a vicious circle that preserves the inflammatory reaction and promotes kidney destruction. Paricalcitol administration breaks the above mentioned vicious circle and attenuates inflammation, by augmenting VDR expression in renal tubular cells. Then the paricalcitol-activated VDR sequesters NF-κB and prevents the transcription of RANTES.39 TGF-β1 is produced in a latent form and stored in the ECM.40 Activated TGF-β1 binds its receptor, enters the nucleus and activates transcription of various genes including those required for myofibroblast formation, components of the extracellular matrix (ECM), and connective tissue growth factor.41 Apart from the above mentioned classical TGF-β1 signal pathways, many other pathways also exist.42 Monocyte chemoattractant protein-1 promotes macrophage infiltration in the kidney, a problem seen in a number of kidney diseases. Macrophages release many factors that promote kidney disease progression. At the molecular level, 1,25(OH)2-D3 inhibits the high glucose-induced monocyte chemoattractant protein-1 and angiotensinogen expressions and inflammation-induced plasminogen activator inhibitor-1 expression by blocking the activation of NF-κB.43
The VDR agonists can also decrease macrophage infiltration, oxidative stress and levels of proinflammatory cytokines and profibrotic growth factors. Studies in in vitro and in vivo experimental models of renal diseases confirmed that VDR agonists decreased TGF-β1 and its type I receptor expressions.44In vitro studies showed that active VDR agonists decreased cytokine produced by human blood mononuclear cells after various inflammatory stimuli.45,46 In the clinic, administration of an active VDR agonist decreased C-reactive protein in patients with kidney failure.47
VDR and proteinuria
It is now widely accepted that proteinuria is a good prognostic marker in the progression of choric kidney disease. A cross-sectional analysis of the NHANES III data revealed a correlation between vitamin D insufficiency and increased prevalence of albuminuria in the US adult population, suggesting that vitamin D has an intrinsic antiproteinuric activity.48 A number of clinical studies have demonstrated therapeutic efficacy of 1,25(OH)2-D3 analogs in reducing proteinuria. VDR agonists have also been shown to decrease proteinuria in human subjects with chronic kidney disease,47,49-50 and improve survival in patients with ESRD.51 A recent large scale randomized controlled study (VITAL) in patients with type 2 diabetes mellitus who have already been treated with ACE inhibitors of ARBs showed that treatment with paricalcitol (a synthetic vitamin D2 agonist) resulted in a significant reduction of urinary albumin.52
These studies indicate that VDR agonists are also highly beneficial in human subjects with diabetic or non-diabetic kidney disease, suggesting that combination of an ACE inhibitor or an ANG II receptor blocker with a VDR agonists would be a good therapeutic option. At this time, the combination treatments may be considered an adjunctive measure in addition to RAS blockade and blood pressure control.53
Podocytes play a key role in the regulation of glomerular filtration in the kidney. The foot processes of podocytes are an integral part of the glomerular filtration barrier that prevents proteins and other large molecules from being filtered into the urine.54 Wang's study provides strong evidence suggesting that vitamin D/VDR signaling in podocytes plays a critical role in the protection of the kidney from diabetic injuries. DBA/2J mice overexpressing human vitamin D receptor (hVDR) were used in this study. After the induction of diabetes with streptozotocin, the transgenic mice had less albuminuria than wild-type controls. In transgenic mice, a low dose of the vitamin D analog doxercalciferol prevented albuminuria occurrence, attenuated podocyte loss and apoptosis and reduced glomerular fibrosis. But the same dose of vitamin D had little effect on the progression of diabetic nephropathy in wild-type mice. Moreover, reconstitution of VDR-null mice with the hVDR transgene in podocytes rescued the VDR-null mice from severe diabetes-related renal damages.55
Furthermore, another novel finding of Wang's study is that activation of VDR results in decreased neutral lipids (triglycerides and cholesterol) accumulation and adipophilin expression in the kidney by downregulating sterol regulatory element binding protein 1 and 2 and their target enzymes that mediate fatty acid and cholesterol synthesis.56
As a major chronic complication of diabetic mellitus, DN is the most common cause of ESRD and associated with the highest mortality across racial and ethnic groups. In spite of all the beneficial interventions implemented in patients with diabetes, DN progresses in most of these patients.57 Over the last decade there has been considerable evolution of our understanding of 1,25(OH)2-D3 metabolism and its biological activities. Our study suggests that the VDR has many beneficial functions in improving RAS, inflammation, fibrosis, proteinuria and lipid metabolism, therefore, exhibits a great potential for preventing the progression of DN. Most recent studies have shown that vitamin D analogues have excellent therapeutic potentials when used in a novel combination therapy with RAS inhibitors. These data shed new light on therapeutic interventions of DN, which have enormous clinical implications.
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