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University of Groningen

The Vitamin D – Fibroblast Growth Factor 23 – Klotho Axis and Progression of ChronicKidney DiseaseMirkovic, Katarina

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Chapter 2

Vitamin D in Chronic Kidney Disease: New Potentialfor Intervention

Katarina Mirković, Jacob van den Born, Gerjan Navis and MartinH. de Borst

Curr Drug Targets. 2011 Jan; 12(1): 42-53.

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ABSTRACT

Prevention of progressive renal function loss and its complications remains themain challenge in clinical nephrology. Although current therapeutic strategies aimingat reduction of blood pressure and proteinuria often slow down deterioration of renalfunction, still many patients progress to end-stage renal disease. The development ofnovel pharmacological approaches for treatment of chronic kidney disease (CKD) istherefore instrumental. Here we review the renoprotective potential of vitamin D andits analogues. In CKD patients, vitamin D deficiency is common and progression ofCKD is associated with low (active) vitamin D levels. Moreover, in animal modelsof CKD, treatment with vitamin D (analogues) alone or in combination with renin-angiotensin-aldosterone system (RAAS) blockade reduces proteinuria, glomerulosclerosisand tubulointerstitial fibrosis. Potential underlying mechanisms include suppression ofthe RAAS, modulation of immune cell function and direct protective effects on renalcells such as podocytes. Whether vitamin D analogues could further optimize existingtherapies in human renal disease is currently under investigation.

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Vitamin D in Chronic Kidney Disease

2.1 Introduction

Prevention of progressive deterioration of renal function and its complications remains themain challenge in clinical nephrology. According to Kidney Disease Outcomes Quality Ini-tiative (K/DOQI) guidelines, chronic kidney disease (CKD) is defined either by reducedkidney function or by the presence or absence of kidney damage -irrespective of etiology1. Severity of CKD can be classified in 5 stages - according to the level of glomerularfiltration rate and the presence of markers of kidney damage such as (micro-)albuminuria.Progression of CKD may lead to end-stage renal disease (ESRD), requiring renal replace-ment therapy such as dialysis or transplantation. The prevalence of CKD, estimated fromdata in NHANES III (Third National Health and Nutrition Examination Survey) is about11% of the general population in the United States 2. These data are comparable betweenUnited States and European countries 3.

Therapeutic strategies aiming at reduction of blood pressure and proteinuria by block-ade of the renin-angiotensin-aldosterone system (RAAS) 4−6 combined with adequatecontrol of volume status (i.e. low sodium diet or diuretics) 7−9 have been shown benefi-cial in slowing down the progression of CKD. However, in many patients RAAS blockadeonly delays ESRD but does not prevent it. Therefore, in spite of good therapy response,reflected by reduction of proteinuria and blood pressure, the protection against ongoingrenal damage is incomplete. Consequently, the prevalence of ESRD is still growing. Resis-tance to therapy may be explained by adverse effects of RAAS-blockade such as a reactiverise in renin and aldosterone levels eliciting pro-inflammatory and pro-fibrotic effects 10,11.Moreover, efficacy of antiproteinuric therapy is determined by the extent of pre-treatmentrenal damage 12,13. Novel treatment strategies in CKD, especially strategies to overcomeresistance to RAAS-related therapy, are warranted.

This chapter will address the potential role of active vitamin D (analogues) as (addi-tional) therapy in CKD. Until recently, active vitamin D was used mainly for correctionof secondary hyperparathyroidism in CKD patients. However, besides the classical viewon this hormone as a regulator of mineral metabolism, recent evidence point to other im-portant functions in different target organs including the renal and cardiovascular system,and regulation of the immune response.

This chapter first gives a brief overview of physiology and biological functions of vita-min D. Mechanisms and pathogenic consequences of vitamin D deficiency in CKD will alsobe discussed. The main focus, however, is on the renoprotective effects of active vitaminD and its analogues, possible underlying mechanisms, and their potential to overcometherapy resistance.

2.2 Vitamin D Physiology

2.2.1 Production and Metabolism

Vitamin D is a steroid prohormone produced in the skin from cholesterol-derived precur-sors (i.e. 7-dehydrocholes-terol) through a photochemical process. Alternatively, vitaminD can be obtained from dietary sources such as fortified dairy products, fish oils andmushrooms (Figure 2.1) Two native, biologically inactive, forms of vitamin D are vitaminD3 (cholecalciferol) derived from the skin and animal products and vitamin D2 (ergocal-

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Figure 2.1: Vitamin D production and metabolism. Vitamin D is produced photochemicallyfrom its precursors in the presence of solar ultraviolet B radiation. Alternatively, it can beabsorbed by the intestine from a variety of dietary sources. Conversion into biologically activeform takes place in the liver and the kidney, via two hydroxylation steps. Enzyme 1α-hydroxylaseis expressed in many other cells besides the proximal tubular epithelial cells of the kidney. Activevitamin D is inactivated by addition of another hydroxyl group at position C24. This ultimatelyleads to a production of water-soluble calcitroic acid, excreted by the kidney.

ciferol) of non-animal origin. It has been suggested that these forms are not bioequivalentdue to the differences in their side chains 14,15. However, a recent study showed thatboth vitamin D2 and D3 are equally effective in maintaining circulating concentrations of25-hydroxy vitamin D and exert identical biological roles 16.

The main plasma carrier for vitamin D metabolites is vitamin D-binding protein(VDBP) 17. VDBP has the highest affinity for 25-hydroxy vitamin D [25(OH)D], andvirtually all plasma 25(OH)D is bound to VDBP 18. VDBP also functions to maintainstable serum stores of vitamin D metabolites and modulate their bioavailability, therebyinfluencing responsiveness of target cells to vitamin D and its analogues 19. VDBP-boundvitamin D metabolites have limited access to target cells and longer half-life in the cir-culation which might have important clinical implications given the fact that vitaminD analogues differ in their VDBP-binding capacity. In healthy individuals, the VDBP-vitamin D complex is filtered by the glomerulus in the kidney, and fully reabsorbed byproximal tubular cells via receptor-mediated uptake by megalin 20,21. Another proteininvolved in this process is cubulin which facilitates endocytosis by sequestering 25(OH)D-VDBP complex to the cell surface before internalization by megalin 22.

The biologically active form of vitamin D is 1α, 25−dihydroxyvitamin D [1, 25(OH)2D]or calcitriol. Conversion into the active form consists of two hydroxylation steps catalyzedby mitochondrial and/or microsomal cytochrome P450 (CYP) isoforms. In the liver,

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pro-vitamin D is converted to 25-hydroxyvitamin D or calcidiol by the 25-hydroxylases(CYP3A4, CYP2R1, CYP2J3 and CYP27A1) 23. These enzymes differ in their affinityand specificity for the substrate. The physiological relevance of different 25-hydroxylasesin vitamin D metabolism is not fully elucidated. The first hydroxylation step is mainlysubstrate dependent and 25(OH)D is the main circulating form of vitamin D; conse-quently, serum concentration of 25(OH)D serves as an indicator of vitamin D status 24.In the second hydroxylation step, 25(OH)D is converted into the biologically active form1, 25(OH)2D. The key enzyme in this process is 25-hydroxyvitamin D−1α−droxylase(1α-hydroxylase, CYP27B1), expressed primarily in proximal tubular epithelial cells ofthe kidney 25. This enzyme is expressed in other parts of the kidney and extra-renal tis-sues and cells as well 26. In these tissues, via local activation by 1α-hydroxylase, vitaminD functions as a paracrine or autocrine factor mediating different cellular processes. Thefinal step in the vitamin D metabolic pathway is its inactivation, a process catalyzedby 24-hydroxylase (CYP24A1) that catabolizes both 1, 25(OH)2D and 25(OH)D into1, 24, 25(OH)3D and ultimately water-soluble calcitroic acid and inactiveblood metabo-lite 24, 25(OH)3D

27,28.

Proximal tubular cells of the kidney are the main site of 1, 25(OH)2D synthesis forsystemic needs and their circulating levels are tightly regulated via several feedback mech-anisms (Figure 2.2). First, 1, 25(OH)2D negatively regulates its own levels by induction ofCYP24A1 in target cells, thereby preventing toxicity. Evidence from CYP24A1 knockoutmice supports this 29. On the other hand, renal 1α-hydroxylase also has an important rolein regulation of circulating 1, 25(OH)2D levels. Expression and activity of this enzymeis positively regulated by parathyroid hormone (PTH) and calcitonin 30,31, depending onthe serum calcium levels. Active vitamin D itself negatively regulates expression of 1α-hydroxylase, either directly via vitamin D receptor mediated repression of 1α-hydroxylasegene transcription 32 or through downregulation of PTH. In addition, 1, 25(OH)2D inducesthe production of FGF23 (fibroblast growth factor 23) in osteocytes which acts throughFGFR1-Klotho complex to negatively regulate renal expression of 1α-hydroxylase andinfluences its own synthesis 33−35.

2.2.2 Mechanisms of Action

Active vitamin D mediates its biological effects by binding to vitamin D receptor (VDR).The VDR is a ligand-dependant transcriptional factor, predominantly located in the nu-cleus. However, unliganded VDR may be partitioned between the cytoplasm and nucleusand 1, 25(OH)2D induces its translocation to the nucleus

36. The VDR is a member of thenuclear receptor superfamily and exhibits the same modular structure as other membersof the superfamily 37. VDR regulates transcription of target genes through heterodimer-ization with retinoid X receptors (RXRs). VDR/RXR heterodimers interact with specificsequences generally in the promoter region of the target genes. These sequences areknown as vitamin D response elements (VDREs) and binding of vitamin D-VDR com-plexes to these sequences leads to induction of gene expression. Alternatively, the VDRmay also repress the expression of target genes, via negative vitamin D response elementsand interaction with corepressors. Genes like CYP27B1 32 and PTH 38 are thought tobe regulated by negative VDREs. Analysis of VDR target genes identified over 200 pri-mary 1, 25(OH)2D -responding genes involved in different cellular processes such as cell

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Figure 2.2: Regulation of 1α-hydroxylase and circulating levels of vitamin D. Circulating levelsof active vitamin D depend both on its synthesis from precursors and the rate of its degra-dation to a non-functional metabolite, catalyzed by enzymes 1α-hydroxylase (CYP27B1) and24-hydroxylase (CYP24A1) respectively. 1α-hydroxylase is upregulated by parathyroid hormone(PTH) and calcitonin and downregulated by fibroblast growth factor 23 (FGF23). Active vitaminD regulates 1α-hydroxylase either by direct suppression of 1α-hydroxylase gene transcription orby feedback mechanisms via PTH and FGF23. Also, active vitamin D is the most potent inducerof its own degrading enzyme 24-hydroxylase.

metabolism, growth and differentiation and control of bone formation and inflammation39.

Besides genomic actions, 1, 25(OH)2D may also exert so-called rapid or non-genomicresponses, mediated via a membrane form of VDR associated with caveolae of the plasmamembrane 40. The membrane-associated VDR is probably the same as the classical VDR,expressed in various tissues of different species. Non-genomic effects occur within secondsto minutes and are independent of transcription or translation 41. These effects includechanges in calcium flux through interaction with calcium channels, release of calcium fromintra-cellular stores (i.e. endoplasmatic reticulum), induction of second messenger systemand activation of cytosolic kinases. Involvement of the VDR in these pathways is still underdebate, as rapid responses of 1, 25(OH)2D may be induced in the cells lacking a VDR

42. Inaddition, non-genomic actions of 1, 25(OH)2D may modulate VDR-dependent gene tran-scription and this in turn may influence cell-specific biological responses to 1, 25(OH)2D43.

The VDR is expressed in over 30 different tissues 44 including the kidney 45. In thenormal human kidney, VDR is expressed in proximal and distal tubular epithelial cells,

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glomerular parietal cells and collecting duct cells 45. Moreover, treatment of culturedmesangial cells 46, podocytes and juxtaglomerular cells 47 with active vitamin D or its24, 25(OH)2D analogues, modulates expression of target genes, suggesting the presence ofa functional VDR in these cells. Analysis of gene expression profile in the kidney of VDRknockout mice revealed 95 differentially expressed genes when compared to the kidney ofthe wild-type mice 48. These genes are involved in vitamin D metabolism, mineral andvolume homeostasis, cellular signaling, cell adhesion, and immune response. However, thequestion remains if all of these genes are primarily responsive or their altered expressionmay be associated with VDR inactivation. Nevertheless, this indicates that active vitaminD has at least some local renal effects.

2.2.3 Biological Functions of Vitamin D

The best-defined physiological function of 1, 25(OH)2D is regulation of calcium and phos-phate homeostasis and promotion of bone mineralization and is reviewed elsewhere 49.In short, 1, 25(OH)2D stimulates active absorption of calcium and phosphate from theintestine and their reabsoption by the kidney, suppresses parathyroid hormone synthesisand cell growth and controls bone remodeling to maintain calcium levels within normalextracellular limits. Vitamin D deficiency results in increased levels of PTH and increasedbone demineralization which ultimately leads to development of rickets in children andosteomalacia in adults 50.

The widespread presence of VDR and vitamin D metabolizing enzymes as well as largenumbers of responsive genes extend the role of this hormone beyond the classical targettissues and control of mineral metabolism. Non-classical functions include regulationof cell proliferation and differentiation, apoptosis, regulation of immune responses andinflammatory pathways and other cell and tissue specific effects (Figure 2.3). Conversely,1, 25(OH)2D and its analogues attract much attention as potential therapeutic agents ina number of human diseases such as cancer, autoimmune diseases and recently CKD.

The biological functions of 1, 25(OH)2D and the effects of vitamin D deficiency canbe studied by vitamin D metabolic pathway knockout mice (Table 2.1) VDR 51,52 and1α-hydroxylase 53,54 knockout mice develop severe vitamin D deficiency, osteomalacia,hypocalcemia and hyper-parathyroidism. In addition, they have an impaired immunesystem and are more prone to autoimmune diseases and tumors. Both VDR-and 1α-hydroxylase-deficient mice have increased renin expression leading to high plasma an-giotensin II levels, hypertension and finally cardiac hyper-trophy. VDR null mice alsodevelop more severe nephropathy after streptozotocin-induced diabetes characterized byoveractivation of the RAAS, increased proteinuria and decreased podocyte number. Therelevance of active vitamin D as a negative regulator of the RAAS and its effects on modu-lation of immune response in terms of renal protection are discussed below in more detail.Due to the disruption of vitamin D catabolic pathway, CYP24A1 knockout mice developlethal hypercalcemia secondary to hypervitaminosis D and impaired bone mineralization29. Chronic exposure to 1, 25(OH)2D induces abnormal kidney histology, consistent withhypervitaminosis D. This phenotype can be rescued by crossing CYP24A1 knockout micewith mice carrying targeted mutation in the VDR. On the other hand, transgenic ratsconstitutively expressing CYP24A1 show somewhat unexpected phenotype with low lev-els of circulating 25(OH)D and 24, 25(OH)2D , hyperlipidemia and albuminuria

55. A

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Table 2.1: Systemic and Kidney Specific Effects of Genetic Intervention in Vitamin D System.

Figure 2.3: Overview of biological functions of vitamin D.

possible explanation for the observed low 25(OH)D levels is that excreted albumin com-petes with 25(OH)D-VDBP complexes for binding to megalin resulting in a urinary lossof 25(OH)D. Plasma levels of 1, 25(OH)2D remained unchanged probably due to observedupregulation of renal 1α-hydroxylase in transgenic rats 56. Interestingly, aged transgenicanimals develop tubular injury, probably as a consequence of proteinuria.

2.3 Vitamin D System in Renal Disease

The kidney plays a central role in vitamin D metabolism and regulation of circulating levelsof this hormone. Therefore, impaired renal function may lead to vitamin D deficiency, asseen in patients with CKD.

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Vitamin D deficiency is common in patients with CKD, is observed even at the earlystages of the disease 57, and is more pronounced than in general population 58−60. Thus,it is important to identify specific factors that may cause vitamin D deficiency in CKDpatients. This probably results from multiple factors. A major determinant of low cir-culating levels of 1, 25(OH)2D in CKD patients is reduced activity of 1α-hydroxylaseresulting from the reduction in renal mass and tubular dysfunction 61. Another inter-esting hypothesis is that urinary loss of 25(OH)D-VDBP associated with proteinuria andreduced megalin-mediated uptake might result in vitamin D deficiency. Megalin knockoutmice develop low molecular weight proteinuria and lose large amounts of vitamin D-VDBPcomplexes in their urine which results in severe vitamin D deficiency and skeletal defects20. Kidney-specific megalin knockout mice display a similar phenotype 62. Decrease inmegalin expression may occur early in the progression of chronic kidney disease, as ithas been demonstrated in the model of partial nephrectomy 63. However, so far there isno evidence of reduced megalin expression in patients with renal disease. Alternatively,reduced levels of 25(OH)D might be a result of compromised endogenous pre-vitamin Dproduction in the skin due to uremia 64.

Beside its important role in vitamin D metabolism, the kidney is also one of the primarytarget organs for both endocrine and paracrine actions of this hormone. Thus, it can beassumed that as decline in renal function leads to vitamin D deficiency, deficiency itselfmay exacerbate the disease. Indeed, several studies have demonstrated an independentinverse association between circulating (active) vitamin D levels and progression of renalfunction loss 65−67. Data from the NHANES III demonstrated an association betweenvitamin D deficiency and increased risk of albuminuria 68.

2.4 Renoprotective Effects of Vitamin D andIts Analogues

Emerging evidence from clinical and experimental studies suggests that vitamin D and itsanalogues may have beneficial effects in patients with CKD that are beyond the controlof secondary hyperparathyroidism. Vitamin D and vitamin D receptor analogue (VDRA)therapy has shown to be beneficial and associated with improved survival in hemodialysisas well as non-dialysis patients 69−74. Recent clinical studies demonstrated antiproteinuriceffects of paricalcitol which were independent of concomitant use of RAAS blockers andpossibly PTH independent as well 75,76. Large, randomized, controlled clinical studies toassess the renoprotective potential of VDR activation are currently underway 77.

Results from animal experiments demonstrated renoprotective effects of both activevitamin D and its analogues (Table 2.2). These include direct antiproteinuric effect viaprotection of podocytes, suppression of the renin-angiotensin-aldosteron system, and im-munomodulatory and anti-inflammatory effects. To our knowledge, Schwarz et al.78 werethe first to report reduction of albuminuria and suppression of glomerulosclerosis in subto-tally nephrectomized rats following treatment with calcitriol. In addition, calcitriol treat-ment reduced vascular and tubular TGF-β (transforming growth factor beta) expression.A similar study 79 showed that vitamin D analogue 22-oxa-calcitriol also reduced albu-minuria and glomerulosclerosis. Tubular injury markers such as NAG (N-acetyl-beta-D-glycosaminidase) and β2M (beta(2)-microgloblin) were unaffected. In a rat model of acute

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Table 2.2: Summary of Studies Investigating the Role of Vitamin D and VDRA in Models ofRenal Diseases.

glomerulonephritis induced by anti-Thy1, administration of both active vitamin D and22-oxa-calcitriol lowered proteinuria and degree of glomerulosclerosis via antiproliferative,antifibrotic and anti-inflammatory effects 80−82. It has also been shown that active vitaminD and VDRA can ameliorate renal interstitial fibrosis. In a mouse model of tubulointer-stitial fibrosis induced by unilateral uretheral obstruction paricalcitol reduced interstitialfibrosis and restored VDR expression in the obstructed kidney. Moreover, paricalcitoldirectly inhibited endothelial-to-mesenchymal transition of tubular cells, by direct sup-pression of TGF-β and its receptor 83. Recent studies, in both subtotally nephrectomizedrats 84 and diabetic VDR knockout mice 47 provided evidence that renoprotective effectsof active vitamin D and its analogues are, to some extent mediated via suppression of theRAAS. An overview of renoprotective effects of active vitamin D is shown on Figure 2.4.

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Figure 2.4: Renoprotective effects of active vitamin D and vitamin D analogues. Vitamin Dnegatively regulates renin-angiotensin-aldosterone system (RAAS) by inhibition of renin gene injuxtaglomerular cells, directly preventing its pro-fibrotic effects. Anti-inflammatory effects ofvitamin D are mediated mostly via downregulation of NF-κB pathways in tubular epithelial cellsand macropahges. T-helper-cell responses and maturation and differentiation of dendritic cellsare also affected and modified by active vitamin D. In podocytes, vitamin D exerts protectiveeffects evidenced as upregulation of nephrin and podocin and decrease in podocyte injury markerssuch a desmin. Permission obtained from Nature Publishing Group Ltd© Doorenbos CRC, vanden Born J, Navis G, de Borst MH, Possible renoprotection by vitamin D in chronic renal disease:beyond mineral metabolism Nat. Rev. Nephrol. 5, 691-700 (December 2009).

2.4.1 Direct Antiproteinuric Effects of Active Vitamin D

The podocyte, a highly specialized cell involved in maintenance of glomerular filtrationbarrier 85, has been recognized to mediate progression of glomerular damage and chronickidney disease85−87. Moreover, podocyte injury may be the initial step in the pathogenesisof CKD. Disruption of the integrity of the filtration barrier due to apoptosis or detachmentof podocytes leads to glomerulosclerosis, tubulointerstitial fibrosis and proteinuria 86,88,89.Conversely, proteinuria itself can induce tubular damage. Underlying mechanisms of thisprocess are beyond the scope of current review. In short, ultrafiltrated protein load pro-motes infiltration of inflammatory cells and fibrosis via induction of expression of tubularchemokines and intrarenal activation of the complement system 90. Preventing podocytedamage and resulting proteinuria in kidney disease would be a meaningful therapeuticstrategy.

Recent studies provide evidence for direct antiproteinuric effect of active vitamin Dthrough maintenance of structural and functional integrity of podocytes. Active vitamin Dinduces expression of nephrin (an important slit diaphragm protein) in cultured podocytes

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91, possibly in cooperation with the retinoic acid receptor 92, suggesting active vitamin Dto be a differentiation factor for podocytes.

In subtotally nephrectomized rats, Kuhlman et al.93, showed that treatment withactive vitamin D markedly decreased podocyte loss and ameliorated morphological andimmunohistochemical markers of podocyte damage such as desmin but whether this isa direct effect remains inconclusive. On the other hand, in the puromycin aminonucle-oside nephrosis model, characterized by podocyte loss and massive proteinuria withoutmesangial proliferation and matrix accumulation, treatment with active vitamin D or itsanalogue 22-oxacalcitriol demonstrated a clear antiproteinuric effect. Moreover, admin-istration of vitamin D partially restored expression of nephrin and podocin (moleculeassociated with the slit diaphragm) and decreased expression of desmin (podocyte injurymarker) 94,95. Taken together, these studies suggest that active vitamin D exerts directprotective effect on podocytes, which contributes to its overall renoprotection. However,the possibility of indirect effects through interference with the RAAS cannot be excluded.In support of this, it should be mentioned that transgenic rats overexpressing angiotensinII receptor type I (AT1R) on podocytes develop proteinuria and structural podocyte dam-age that results in glomerulosclerosis 96.

2.4.2 RAAS-Related Effects of Vitamin D

The RAAS plays a major role in the pathophysiology of kidney disease 97. Regardless theprimary cause, initial renal injury may result in progressive loss of nephrons and hyperfil-tration and glomerular hypertension, which induces local stimulation of the RAAS. Themain effector molecule of this system is angiotensin II (AngII). Ang II acts as a vasocon-strictor and exerts profibrotic and proinflammatory effects. In the kidney, AngII increasesintraglomerular pressure and induces pro-inflammatory and pro-fibrotic cytokines andgrowth factors like TGF-β 98, plasminogen activator inhibitor-1 (PAI-1) 99 and monocytechemotactic protein-1 (MCP-1) 100. These events result in proteinuria, glomerulosclero-sis and tubulointerstitial fibrosis and promote further deterioration of renal function andultimately renal failure.

An inverse relationship between 1, 25(OH)2D levels and high blood pressure and reninactivity has been documented two decades ago 101−103. Whether VDRA exert antihy-pertensive effects is still debatable 104 and beyond the scope of this paper. However,emerging evidence points to active vitamin D as negative regulator of the RAAS. BothVDR knockout and 1α-hydroxylase knockout mice display increased renal renin mRNAand protein levels 105,106. Subsequent treatment of 1α-hydroxylase knockout mice withactive vitamin D restores normal renin levels. This effect appears to be independent ofcalcium and PTH 107. Normal mice with induced vitamin D deficiency also have increasedrenin levels and treatment with active vitamin D results in renin suppression 105. In ad-dition, VDR knockout mice develop hypertension, probably because of RAAS activation.AngII levels are elevated as a consequence of high renin levels because there is no dif-ference in angiotensinogen expression in the liver between knockout and wild type mice.Together, these results suggest that vitamin D directly suppresses renin expression in vivo.Treatment of VDR knockout mice with angiotensin-converting enzyme inhibitors (ACEi)or/and AT1R blockers (ARB) reverses high blood pressure phenotype but renin levels re-main elevated 108. This indicates that repression of renin expression by active vitamin D

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is independent of the AngII feedback loop. At the molecular level, active vitamin D neg-atively regulates renin expression at the transcriptional level by binding to the promoterregion of the renin gene 105 and blocking the activity of the cAMP response element inthe promoter region 109. It has been shown that vitamin D, at least in adipocytes, down-regulates the expression of AT1R in a dose-dependent manner 110. At this time, there isno evidence to suggest the existence of similar interactions in renal cells.

RAAS blockade by ACEi and ARB is currently therapy of choice for patients with CKD111. The beneficial effect of RAAS blockade on blood pressure and proteinuria can be po-tentiated by volume-depleting measures such as low sodium diet and/or administrationof diuretics 112,113. Higher doses and combined blockade of ACE and AT1R were foundeffective to reduce proteinuria. However, the limits of further improvement of renoprotec-tion by RAAS blockade based therapy might have been reached, whereas in many patientsresidual proteinuria and progression towards end-stage renal disease remains 114,115.

Due to multiple feedback loops and alternative routes within the RAAS, inhibitionof this system at one level leads to compensatory responses at other levels resulting insuboptimal therapeutic efficacy 116. Besides AngII, also aldosterone 117 and renin 118,the latter possibly through the recently discovered (pro)-renin receptor (PPR), also ex-ert proinflammatory and pro-fibrotic effects. In addition, results from animal studiesshowed dissociation between improvement of blood pressure and proteinuria during in-tensified RAAS blockade on the one hand, and worsening of interstitial fibrosis on theother hand 119. This may be due to the elevated levels of renin during intensified RAASblockade. Interestingly, reactive rise of renin is followed by de novo expression of the(pro)-renin receptor in interstitial fibrotic areas 120. These data suggest that any inter-vention that blunts or prevents reactive rise in renin during RAAS blockade may improverenoprotection. Several recent studies indicated that addition of aliskiren to conventionalRAAS blockade enhances renoprotection 121−123 but long-term effects of this therapeuticapproach remain to be established 124. It should be mentioned that while direct renininhibitors such as aliskiren, inhibit only enzymatic activity of renin without affecting itsproduction or its interaction with the PPR 125, active vitamin D directly inhibits reninproduction by repressing renin gene transcription. This implicates that addition of aVDRA to RAAS blockade may indeed improve its efficacy by blocking the reactive risein renin (and downstream aldosterone). This would allow potentiation of therapeutic ef-fects of the RAAS blockade without a reactive rise in renin. Several studies addressedthe effects of combined treatment of VDRA and RAAS blockade in both diabetic andnon-diabetic models of renal injury. Mizobuchi et al. 126 showed that combination ofparicalcitol and ACEi reduced renal damage more effectively than either paricalcitol orACEi alone. This treatment also reduced glomerulosclerosis and suppressed the TGF-βpathway. Similarly, in a model of diabetic nephropathy, combination therapy of paricalci-tol and ARB markedly reduced renal injury due to blockade of the compensatory increasein renin levels 127. Therefore, inhibition of local renin production by VDRA may havetherapeutic potential for patients with CKD.

Given the pleiotropic actions of active vitamin D, however, its renoprotective effectmay not be limited to regulation of the RAAS. Anti-inflammatory properties of vitaminD may also be important for its renoprotective effect in addition to down regulation of theRAAS, as inflammation has been shown to be a determinant of RAAS blockade resistance13,128.

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2.4.3 Anti-Inflammatory and Immuno-Modulatory Propertiesof Vitamin D

The concept of active vitamin D as an immuno-modulatory molecule was first postulatedin the 1980s 129,130. Underlying mechanisms and the relevance of these effects on theprogression and treatment of renal disease have been uncertain for a long time 131. Recentstudies have provided important information on the anti-inflammatory properties andmechanisms of action of vitamin D. Several studies have demonstrated the role of activevitamin D in the modulation of renal inflammation 78,83,132. In a recent study, Zehnderet al. reported that plasma active vitamin D status is inversely associated with renalinflammation in several types of kidney disease 133.

Anti-inflammatory properties of active vitamin D and its analogues may be attributedto their ability to suppress the NF-κB pathway. The NF-κB pathway plays an importantrole in the progression of renal disease by promoting both inflammation and fibrogenesisvia regulation of inflammatory cytokines and chemokines (MCP-1, TNFα, PAI-1) 134.Different stimuli, such as bacterial LPS (lipopoly-saccharide), IL-1β (interleukin-1 beta)and TNF-α (tumor necrosis factor alpha) have been known to activate NF-κB pathway inthe kidney. In addition, both angiotensin II and angiotensin degradation products wereshown to activate NF-κB 135−137. Treatment of cultured proximal epithelial cells withparicalcitol induces formation of complex consisting of VDR and NF-κB p65 componentthus reducing its binding to promoter regions of the target genes 138. This results indecreased activation of genes such as CCL5 [chemokine (C-C motif) ligand 5, RANTES]and subsequently in amelioration of renal inflammation in vivo. Similarly, in mesangialcells administration of active vitamin D inhibits induction and activity of MCP-1 (CCL2)through increase or stabilization of the NF-κB inhibitory unit IκB thus preventing nucleartranslocation of p65 NF-κB unit 46. The reason behind the discrepancy in mechanismsof downregulation of NF-κB signalling pathway remains uncertain and can be attributedto cell-type specificity 138. Interestingly, other signalling pathways, such as c-Jun N-terminal kinase 138,139 and p38 pathways 140 that have been shown to mediate renaldamage, modulate VDR expression 141 as well; the relevance of these interactions in renalcells remains to be determined.

In addition to processing in the liver and the kidneys, vitamin D can be metabo-lized by the cells of the immune system. Active T-cells, macrophages/monocytes andsome dendritic cells express VDR and vitamin D metabolizing enzymes, 1α-hydroxylaseand 24-hydroxylase. In contrast to its regulation in the kidney, activity of extrarenal1α-hydroxylase is mostly substrate dependent. Locally produced active vitamin D mayact on immune cells in an autocrine or paracrine manner 142. In macrophages, both1, 25(OH)2D 3 and its less calcaemic analogue 1, 25(OH)2D suppress NF-κB activity byup-regulating expression of IκB through stabilization of IκB-mRNA and reduction of itsphosphorylation. This results in inhibition of inflammatory genes such as TNFα 143,144.Active vitamin D exerts direct effect on T-helper-1 (Th1) and T-helper-1 (Th2) cells byinhibiting their proliferation and production of cytokines. Key cytokines of Th1-cells,IFN-γ (interferon gamma) and IL-2 (interleukin 2) are direct targets of active vitamin D.Active vitamin D can modulate Th2-cell responses both indirectly, through suppressionof IFN-γ and IL-2 by Th1-cells and directly by influencing expression of Th2 cytokinessuch as IL-4 (interleukin 4). Moreover, it has been shown that active vitamin D inhibits

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expression of Fas ligand by activated T-cells 145. Active vitamin D affects T-cell responsesalso by direct inhibition of maturation, differentiation and activation of dendritic cells 146.This leads to down-regulation of MHC class II and costimulatory molecules and decreaseof dendritic cell dependant T-cell activation. In addition, vitamin D may have an im-portant role in promotion of dendritic cell tolerogenicity 147,148. The role of dendriticcells in the kidney and their contribution to progression of kidney disease is not fullyelucidated. However, a recent study demonstrated their importance in the progression ofglomerulonephritis after glomerular injury 149. Since vitamin D inhibits maturation anddifferentiation of dendritic cells, it might be expected that treatment with vitamin D orits analogues may reduce the immune response.

Together, these findings indicate that vitamin D or its analogues might be usefulfor the treatment of inflammatory and autoimmune diseases including inflammatory kid-ney diseases such as autoimmune nephritis. Moreover, given its anti-inflammatory andimmuno-modulatory properties, vitamin D could also have important role in patients withnon-autoimmune CKD.

2.5 Summary and Conclusions

Prevention of renal function loss and its complications remains the main challenge inclinical nephrology. Current therapy options (i.e. blockade of the RAAS) aim to reducehypertension and proteinuria; nevertheless, many patients develop end-stage renal dis-ease on the long term. Resistance to the therapy may be due to inappropriate effectsof the RAAS blockade, such as reactive rise in renin and aldosterone with possible pro-fibrotic effects. Therefore, there is an increased interest in finding novel treatments thatare able to halt progression of renal function loss or even improve renal function. Grow-ing evidence indicates that vitamin D may have therapeutic potential for patients withCKD that extends beyond its classical role in maintenance of mineral homeostasis andthe present use of active vitamin D for the treatment of secondary hyperparathyroidismin CKD. Moreover, vitamin D deficiency is common in CKD patients and in fact maycontribute to deterioration of the kidney function. Renoprotective effects of vitamin Dand its analogues include suppression of the RAAS and reduction of proteinuria, eitherdirectly through the protection of podocytes or via negative regulation of the RAAS. Inaddition, vitamin D exerts anti-inflammatory and immuno-modulatory effects. Therefore,addition of vitamin D to conventional therapy may present a promising treatment modal-ity. Results of randomized, controlled trials addressing renoprotective potential of thisapproach are expected in the near future.

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