Vitamin D receptor: A highly versatile nuclear receptor

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Vitamin D receptor: A highly versatile nuclear receptor JR Wu-Wong1 Vitamin D receptor (VDR) modulators are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). The therapy is associated with reduced mortality in stage 5 CKD patients, who experience an extremely high cardiovascular disease (CVD)-related mortality rate. Chen et al. report that VDR is involved in regulating type A natriuretic peptide receptor (NPR-A) in inner medullary collecting duct cells. The regulation of NPR-A may be one of several mechanisms by which VDR activation reduces CVD risk in CKD. Kidney International (2007) 72, 237–239. doi:10.1038/sj.ki.5002428

Introduction

Vitamin D3 is made from 7-dehydrocholesterol in the skin after exposure to ultraviolet light and is modified by vitamin D 3-25-hydroxylase in the liver and then by 25-hydroxyvitamin D 3 -1α-hydroxylase (CYP27B1) that resides mainly in the proximal renal tubule to form the active hormone, 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol exerts its functions via binding to a nuclear receptor, the vitamin D receptor (VDR). The binding of calcitriol to VDR activates the receptor to recruit cofactors to form a complex that binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription. During the past three decades, the main focus in the VDR field has been to elucidate its role in regulating mineral homeostasis. Consequently, calcitriol and its analogues, such as alfacalcidol, doxercalciferol, and paricalcitol, are used clinically for the treatment of hyperparathyroidism secondary to chronic kidney disease (CKD). 1Department of Pharmacy Practice, University of

Illinois at Chicago, Chicago, Illinois, USA Correspondence: JR Wu-Wong, Department of Pharmacy Practice, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 606127230, USA. E-mail: [email protected] Kidney International (2007) 72

VDR modulator therapy associated with survival benefit in chronic kidney disease

It is well documented that stage 3 to stage 5 CKD patients encounter a much higher risk of cardiovascular disease (CVD) than the general public and experience an extremely high CVD-related mortality rate. Recent clinical observations, albeit retrospective, found that VDR modulator therapy is associated with a survival benefit for stage 5 CKD patients. Kalantar-Zadeh et al.1 showed in 2006 that, in a 2-year cohort of 58,058 maintenance hemodialysis patients, administration of any dose of paricalcitol was associated with improved survival in time-varying models. Tentori et al.2 showed that, in a 5-year cohort of 7,731 hemodialysis patients, doxercalciferol treatment was also associated with improved survival. Two previous reports by Teng et al.3,4 demonstrated very similar findings. Furthermore, the survival benefit of VDR modulator therapy may be independent of calcium, phosphorous, and parathyroid hormone levels in the patients. How is VDR modulator therapy associated with a survival benefit in stage 5 CKD? What are the possible mechanisms? Unfortunately, so far the answers remain elusive. Cardiovascular phenotype in VDR knockout mice

VDR has been identified in more than 30 different tissues in the human body,

including adipose tissue, bone marrow, cardiomyocytes, the immune system’s B and T lymphocytes, renal cells, and vascular smooth muscle cells, implying that VDR may be involved in regulating a variety of biophysiological functions besides mineral homeostasis. Indeed, VDR knockout mice, in addition to the expected phenotype (such as abnormal mineral homeostasis), developed hypertension and exhibited increased water consumption and urinary salt excretion. Subsequently, it was shown that the size of left ventricular cardiomyocytes in VDR knockout mice was markedly increased when compared with that in wild-type mice, and levels of atrial natriuretic peptide (ANP) mRNA and circulating ANP were also increased in VDR knockout mice.5 In addition, the thrombomodulin gene in the aorta, liver, and kidney of VDR knockout mice was downregulated, and tissue factor mRNA expression in the liver and kidney was upregulated independent of plasma calcium levels, suggesting that VDR may play roles in regulating fibrinolysis and thrombogenesis.6 Judging from recent publications in the VDR field, the role of VDR activation in the cardiovascular system is becoming an important research area. VDR modulates atrial natriuretic peptide and its receptor

The group led by Gardner at the University of California at San Francisco has been active in investigating VDR-mediated cardiovascular functions for many years. They have previously reported that VDR is expressed in cardiomyocytes, and activation of VDR leads to reduced hypertrophy and suppression of ANP expression and secretion in cardiomyocytes treated with endothelin-1.7 They have also shown that calcitriol amplifies type A natriuretic peptide receptor (NPRA) expression in rat aortic smooth muscle cells.8 In addition, in rats treated with a VDR modulator and infused with ANP, the NPR-A mRNA levels in the inner medulla were significantly increased, along with an increase in urinary cyclic guanosine monophosphate levels, urinary sodium, and urine volume. Following those studies, the group now reports (Chen et al.,9 this issue) that both VDR and CYP27B1 are expressed in cultured 237

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Chronic renal disease

Reduced VDR activation

Abnormal mineral homeostasis

Increased inflammation

Increased thrombogenesis

Vascular dysfunction

De-regulation of ANP/BNP/NPR-A and RAAS

Hypertension Left ventricular hypertrophy Reduced vascular compliance Accelerated arterio/atherosclerosis

Increased CV-related mortality

Figure 1 | Hypothetical mechanisms for mortality related to cardiovascular disease in chronic kidney disease. Chronic kidney disease itself may affect many factors involved in regulation of mineral homeostasis, inflammation, thrombogenesis, vascular function, the renin–angiotensin– aldosterone system (RAAS), and the atrial natriuretic peptide/brain natriuretic peptide (ANP/BNP)– type A natriuretic peptide receptor (NPR-A) pathway. VDR may also play a key role in regulating several of these mechanisms.

inner medullary collecting duct cells, and that treatment of these cells with VDR modulators results in an increase in the NPR-A protein level and in ANP-dependent cyclic guanosine monophosphate production, while mutation of a vitamin D response element upstream of the NPR-A gene results in the loss of VDRmediated NPR-A induction. These new findings are important in that they help us understand more about VDR, a seemingly very versatile nuclear receptor, and its involvement in the cardiovascular system, including regulation of NPR-A. NPR-A is a receptor consisting of a large extracellular ligand-binding domain, a single membrane-spanning segment, and an intracellular signaling domain with a non-catalytic, kinase-like region linked to a guanylyl cyclase. The receptor binds to both ANP and brain natriuretic peptide (BNP). Upon activation, the receptor mediates vasodilation, increased urinary excretion of sodium and water, and suppression of myocardial hypertrophy and fibrosis.10 Thus, the ANP/BNP–NPR-A signaling pathway may play a major role in controlling blood pressure and extracellular fluid volume, and VDR may be one of the upstream gatekeepers for this pathway. 238

VDR regulates other cardiovascular functions

Could the ANP/BNP–NPR-A pathway fully account for the reduced CVD risk in stage 5 CKD patients receiving VDR modulator therapy? Perhaps not. Firstly, these findings are mainly from in vitro cell culture studies with somewhat limited animal data. Secondly, the CVD problems in CKD are complex; decreased VDR activa-

Liver Vitamin D3

25-hydroxyvitamin D3

tion may be just one of the many causal factors. Renal deficiency itself affects numerous elements in the cardiovascular pathophysiology, although the VDR signaling pathway seems involved in several of these mechanisms (Figure 1). Thirdly, VDR affects different functions that are linked to the cardiovascular system. For example, VDR modulators have been shown to downregulate renin,5 inhibit smooth muscle cell proliferation,11 restore uremia-induced endothelial-cell dysfunction,12 reduce left ventricular hypertrophy,13 and so on. Any of these effects can also contribute to the cardiovascular benefits of VDR modulator therapy. Simply put, the regulation of NPR-A may be one of several mechanisms by which VDR activation reduces CVD risk in CKD. VDR-mediated autocrine/paracrine functions

It is curious to note that, in the current study9 and also in previous reports from the same group,8,14,15 the maximal effects of calcitriol in inner medullary collecting duct cells, smooth muscle cells, or cardiomyocytes are observed at relatively high doses (>1 nM), which are higher than the calcitriol concentration in circulation (∼0.1 nM). Are there VDR-mediated autocrine and/or paracrine effects in the cardiovascular system? Previously it has been shown that various extrarenal cells and tissues express CYP27B1. It is also

CYP27B1

1α, 25-dihydroxy-vitamin D3 Proximal renal tubule, (Calcitrol, the hormone) renal and extra renal

Endocrine CKD

Endocrine/ paracrine/ autocrine?

• Cardiovascular • Others • PTH/mineral control

Vitamin D receptor • A nuclear receptor • >30 target tissues

Figure 2 | VDR-mediated autocrine, endocrine, and paracrine effects. Calcitriol is well documented as an endocrine hormone. It may also work as an autocrine/paracrine factor in cardiovascular and other systems. Under normal conditions, many renal and extrarenal cells may be capable of generating calcitriol from 25(OH)D3. In chronic kidney disease (CKD), VDR-mediated endocrine, autocrine, and paracrine effects may be compromised. PTH, parathyroid hormone. Kidney International (2007) 72

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known that the level of 25(OH)D3 in circulation is about ∼1000-fold higher than that of calcitriol. Therefore, under normal conditions, it is conceivable that many renal and extrarenal cells are capable of generating calcitriol from circulating 25(OH)D3 to maintain a high local concentration of calcitriol for VDR-mediated autocrine and/or paracrine functions (Figure 2). However, this hypothesis raises more questions. For example, how does one investigate the significance of these VDRmediated autocrine/paracrine functions in the cardiovascular system? Are these functions impaired in CKD? If yes, at what glomerular filtration rate does this mechanism become impaired? Answers to these questions may help us further understand the benefits of VDR modulator therapy in reducing the CVD risk in CKD. CONCLUSION

In summary, the paper by Chen et al.9 provides interesting data showing that the regulation of NPR-A may be one of the mechanisms by which VDR activation is associated with cardiovascular benefit in CKD.

J Clin Invest 2001; 107: 975–984. 11. Wu-Wong JR, Nakane M, Ma J et al. Effects of vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis 2006; 186: 20–28. 12. Wu-Wong JR, Noonan W, Ma J et al. Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther 2006; 318: 90–98. 13. Park CW, Oh YS, Shin YS et al. Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis

patients with secondary hyperparathyroidism. Am J Kidney Dis 1999; 33: 73–81. 14. Chen S, Costa CH, Nakamura K et al. Vitamin D-dependent suppression of human atrial natriuretic peptide gene promoter activity requires heterodimer assembly. J Biol Chem 1999; 274: 11260–11266. 15. Wu J, Garami M, Cao L et al. 1,25(OH)2D3 suppresses expression and secretion of atrial natriuretic peptide from cardiac myocytes. Am J Physiol 1995; 268: E1108–E1113.

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IgA nephropathy: Immune mechanisms beyond IgA mesangial deposition A Rifai1 IgA nephropathy is attributable to mesangial IgA immune complex deposition. The pathogenic potential of frequently colocalized IgG deposits may depend on polarized T-helper cytokines that modulate Fcγ receptors of infiltrating macrophages, leading to either activation or inhibition that determines glomerular injury. Kidney International (2007) 72, 239–241. doi:10.1038/sj.ki.5002356

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Kalantar-Zadeh K, Kuwae N, Regidor DL et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 2006; 70: 771–780. 2. Tentori F, Hunt WC, Stidley CA et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int 2006; 70: 1858–1865. 3. Teng M, Wolf M, Ofsthun MN et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005; 16: 1115–1125. 4. Teng M, Wolf M, Lowrie E et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003; 349: 446–456. 5. Li YC, Qiao G, Uskokovic M et al. Vitamin D: a negative endocrine regulator of the reninangiotensin system and blood pressure. J Steroid Biochem Mol Biol 2004; 89-90: 387–392. 6. Aihara K, Azuma H, Akaike M et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004; 279: 35798–35802. 7. Wu J, Garami M, Cheng T et al. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelinstimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Invest 1996; 97: 1577–1588. 8. Chen S, Nakamura K, Gardner DG. 1,25Dihydroxyvitamin D inhibits human ANP gene promoter activity. Regul Pept 2005; 128: 197–202. 9. Chen S, Olsen K, Grigsby C, Gardner DG. Vitamin D activates type A natriuretic peptide receptor gene transcription in inner medullary collecting duct cells. Kidney Int 2007; 72: 300–306. 10. Knowles JW, Esposito G, Mao L et al. Pressureindependent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. Kidney International (2007) 72

In the complex web of potential mechanisms implicated in the pathogenesis of IgA nephropathy, IgA glomerular deposits remain the sine qua non phenotype of the disease. Despite almost four decades of clinical and experimental investigations, the immunologic processes that induce and perpetuate glomerular IgA deposition remain a clinical challenge to identify. A decade after Jacque Berger’s seminal report of “IgA glomerular deposits in renal disease,” an experimental animal model was developed demonstrating that polymeric IgA immune complexes lead to IgA glomerular deposits. This was followed by a cascade of clinical investigations that reported IgA immune complexes in the circulation and renal tissues of patients with 1Department of Pathology and Laboratory

Medicine, Lifespan Academic Medical Center, Brown University School of Medicine, Providence, Rhode Island, USA Correspondence: A Rifai, Department of Pathology and Laboratory Medicine, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903, USA. E-mail: [email protected]

IgA nephropathy. Now it is well recognized, as described in a comprehensive clinical review,1 that “primary IgA nephropathy is an immune-complex–mediated glomerulonephritis defined immunohistologically by the presence of glomerular IgA deposits accompanied by a variety of histopathologic lesions.” From this characterization it is implicit that not all IgA immune deposits possess equivalent pathogenic potential, as the glomerular landscape usually represents a wide spectrum that varies from minimal or no lesion to severe sclerosis. Thus, the enigma of glomerular IgA deposition is wrapped in the mystery of absent correlation between the intensity of the IgA deposits and the extent of glomerular injury. The experimental findings of Suzuki et al.2 (this issue) shed new investigative light to unwrap this mystery. Over the years, several valuable experimental models of IgA nephropathy have been developed that have provided insightful clues to the pathogenesis of the disease. Collectively, the experimental immunologic and histopathologic 239