Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease  Adriana S. Dusso, Masanori Tokumoto  Kidney International  Volume 79, Issue 7, Pages 715-729 (April 2011) DOI: 10.1038/ki.2010.543 Copyright © 2011 International Society of Nephrology Terms and Conditions

Figure 1 Vitamin D bioactivation and actions. Classical and nonclassical vitamin D actions require vitamin D conversion to 25-hydroxyvitamin D (25(OH)D, open circle), and its bioactivation to its hormonal form 1,25-dihydroxyvitamin D (calcitriol, diamond) by renal and extrarenal 1-hydroxylase and calcitriol binding to and activation of its receptor, the vitamin D receptor (VDR). Calcitriol-activated VDR binds its partner the retinoic X receptor (RXR, heterodimerization) and vitamin D-responsive elements (VDRE) in the promoter of VDR-responsive genes (DNA binding), and recruits basal transcription factors (B) and co-activator and co-repressor molecules (CoReg) to induce or repress the transcription of vitamin D-responsive genes by RNA polymerase II (transcriptional regulation). The net balance between cellular uptake of calcitriol and/or 25(OH)D, the rate of 25(OH)D conversion to calcitriol versus the activity of 24-hydroxylase (cyp24), responsible for the inactivation of 25(OH)D and calcitriol (crossed blue circle and purple diamond), determines the degree of VDR activation by intracellular calcitriol. Most of these steps are impaired in kidney disease. Ca, calcium; P, phosphate; RAAS, renin-angiotensin-aldosterone system. Kidney International 2011 79, 715-729DOI: (10.1038/ki.2010.543) Copyright © 2011 International Society of Nephrology Terms and Conditions

Figure 2 Central role of renal calcitriol production in mineral and skeletal homeostasis in health. Renal calcitriol (1,25D, black lanes) production tightly controls the complex hormonal feedback loops between parathyroid hormone (PTH; light gray lanes) and fibroblast growth factor 23 (FGF23; dark gray lanes), as well as calcium (Ca; black arrows) and phosphate (P; gray arrows) fluxes between the intestine, bone, and the kidney that ensure normal mineral homeostasis and skeletal integrity, while preventing the excess of both ions predisposing to ectopic calcifications. Kidney disease severely impairs the calcitriol/FGF23/PTH loops (see text for details), as well as the renal uptake of 25-hydroxyvitamin D bound to vitamin D-binding protein (DBP) from the glomerular filtrate to maintain renal calcitriol synthesis. Kidney International 2011 79, 715-729DOI: (10.1038/ki.2010.543) Copyright © 2011 International Society of Nephrology Terms and Conditions

Figure 3 Defective renal 25(OH)D uptake impairs substrate availability to renal 1-hydroxylase in CKD. (a) Circulating 25(OH)D (25D) bound to its carrier vitamin D-binding protein (DBP) is filtered by the kidney and internalized into proximal tubular cells via megalin-mediated endocytosis. Upon its release from DBP, 25(OH)D is either delivered to 1-hydroxylase by intracellular vitamin D-binding protein 3 (IDBP3) for its bioactivation to calcitriol (1,25D) or it re-enters the circulation. Calcitriol induces renal megalin expression, thereby generating a cycle that ensures normal systemic 25(OH)D and calcitriol levels as well as the reabsorption of low-molecular-weight proteins from the glomerular filtrate, including albumin. In chronic kidney disease (CKD), decreases in glomerular filtration rate (GFR) and low megalin content contribute to impair 25(OH)D uptake and protein reabsorption. (b) The strong correlation between serum levels of 25(OH)D and calcitriol (1,25(OH)2D) in severely uremic patients (GFR <25ml/min), which is absent in normal individuals (dotted line), demonstrates impaired 25(OH)D availability for its bioactivation to calcitriol by the remnant renal 1-hydroxylase in CKD. Only supraphysiological concentrations of 25(OH)D normalize serum calcitriol levels. Adapted from reference Halloran et al.41 Kidney International 2011 79, 715-729DOI: (10.1038/ki.2010.543) Copyright © 2011 International Society of Nephrology Terms and Conditions

Figure 4 Calcitriol corrects the impaired 25(OH)D availability to nonrenal 1-hydroxylases in chronic kidney disease (CKD). (a) The strong correlation between serum levels of 25(OH)D and calcitriol (1,25(OH)2D) in bilaterally nephrectomized patients (anephrics) demonstrates impaired 25(OH)D availability for its bioactivation to calcitriol by nonrenal 1-hydroxylases. Only supraphysiological concentrations of 25(OH)D normalize serum calcitriol levels. (b) 25(OH)D uptake (30min) at day 0 (left bar) and at day 15 (right bar) by peripheral blood monocytes from normal individuals (Normal) and hemodialysis patients (Uremic) receiving either vehicle (Controls) or intravenous calcitriol (1,25(OH)2D) three times a week for 15 days. (c) The Vmax of 1-hydroxylase in monocytes from hemodialysis patients, a marker of enzyme content, inversely correlates with serum calcitriol levels, thus demonstrating a tight feedback inhibition of monocyte 1-hydroxylase expression by physiological levels of calcitriol. Adapted from reference Dusso et al.112 Modified from reference Gallieni et al.16 Kidney International 2011 79, 715-729DOI: (10.1038/ki.2010.543) Copyright © 2011 International Society of Nephrology Terms and Conditions

Figure 5 Increases in renal tumor necrosis-α-converting enzyme (TACE) activation cause angiotensin-II (Ang II)-driven renal lesions. Nephron reduction and the binding of Ang II to its heptahelical AT1 receptor (AT1) induce cytosolic TACE activation and its translocation to the cell membrane to release transforming growth factor-α (TGFα), which binds to and activates the epidermal growth factor receptor (EGFR) causing renal lesions. EGFR activation by tyrosine phosphorylation (P-EGFR) stabilizes cytosolic TACE, thereby generating a feed-forward loop of progressive increases in TACE activation and TACE/TGFα-driven renal damage in mouse and human kidney disease. TACE-mediated cleavage and release of the soluble forms of the potent proinflammatory molecules tumor necrosis factor-α (TNFα), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion molecule 1 (VCAM-1) aggravate TGFα-driven renal damage, and provide serum markers of the degree of TACE activation. Kidney International 2011 79, 715-729DOI: (10.1038/ki.2010.543) Copyright © 2011 International Society of Nephrology Terms and Conditions