Evaluating Hormonal Mechanisms of Vitamin D Receptor Agonist Therapy in Diabetic Kidney Disease: The VALIDATE-D Study

Jenifer M Brown; Kristina Secinaro; Jonathan S Williams; Anand Vaidya

Disclosures

BMC Endocr Disord. 2013;13(33) 

In This Article

Background

The link between vitamin D and kidney disease, particularly in the setting of human diabetes, has received much attention.[1,2] Observational and limited interventional studies have supported a renoprotective benefit to higher vitamin D levels and vitamin D supplementation;[3–7] however, there is a need for more dedicated human intervention studies to confirm these findings. One of the main proposed mechanisms linking vitamin D with renal-vascular and kidney disease is regulation of the renin-angiotensin system (RAS).[8,9] Since both of these hormonal systems have complex genetic and environmental regulatory steps (Figure 1), carefully controlled interventional studies that evaluate both mechanisms of action and clinical outcomes are needed to distinguish the hormonal interplay that is likely involved for vitamin D therapy to influence kidney disease.

Figure 1.

The proposed interaction between vitamin D and RAS metabolism. Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is further converted to the vasoactive peptide angiotensin II. Angiotensin II is a direct vasoconstricter, and can also ilicit aldosterone secretion from the adrenal cortex. Under physiologic situations, activation of the RAS in response to renal-vascular hypo-perfusion serves to increase blood pressure and renal salt retention. However, in pathologic states (such as in diabetes and obesity), inappropriately high RAS activity contributes to vascular and kidney diseases. Vitamin D3 is largely produced in the skin with exposure to ultraviolet radiation, but may also be ingested orally. This precursor is hydroxylated to 25-hydroxyvitamin D (25[OH]D) and 25(OH)D serves as the stable barometer of clinical "vitamin D status." Under the control of parathyroid hormone and calcium status, 25(OH)D can be hydroxylated to form the active vitamin D receptor (VDR) agonist 1,25-dihydroxyvitamin D (1,25[OH]2D). Activation of the VDR by 1,25(OH)2D is known to influence the regulation and expression of a myriad of genes, including renin.

Both excess activity of the renin-angiotensin system (RAS) and insufficient vitamin D status have been implicated in the development of renal-vascular disease that results in diabetic nephropathy.[1,2,10] The RAS can mediate renal-vascular disease via its circulating components, and additionally the locally expressed renal-vascular tissue-RAS also contributes to the development of kidney disease.[11,12] Excess renal-vascular tissue-RAS activity has been implicated in the development of diabetic nephropathy; RAS inhibitors,[13–15] as well as favorable vitamin D status,[5,16,17] may mitigate this effect.

Animal studies have shown that the activation of the vitamin D receptor (VDR) by 1,25-dihydroxyvitamin D (1,25[OH]2D) negatively regulates renin expression and thereby lowers RAS activity[9,18] (Figure 1). In mouse models of diabetes, both VDR-agonists and RAS-inhibitors blunted the development of diabetic nephropathy when given alone, but the combination (VDR-agonist + RAS-inhibitor) synergistically prevented the development of diabetic nephropathy via down-regulation of the renal-vascular tissue-RAS.[19–21] We, and others, have reported findings that translate these animal experiments to humans: the combination of vitamin D levels and genetic variation at the human VDR predicts RAS activity.[22–24] Large observational studies have shown that the prevalence of chronic kidney disease and proteinuria (a marker of kidney disease progression) are associated with lower 25(OH)D levels.[3,25,26] Due to their cross-sectional design, these aforementioned studies could not reveal causality or confirm the mechanism linking vitamin D-VDR interactions and renal outcomes. A few human interventions have demonstrated that VDR agonists may reduce proteinuria,[2,7] but these studies were confined to populations with established chronic kidney disease (CKD), and evaluation of the RAS was not undertaken. We recently completed a pilot human intervention study in non-diabetics without CKD that demonstrated that high-dose vitamin D3 therapy improved renal-vascular hemodynamics by lowering renal-vascular tissue-RAS activity.[5] This latter effect was similar to that induced by an angiotensin converting enzyme (ACE) inhibitor, thereby further supporting a renoprotective effect of vitamin D therapy.[5]

In light of these novel human results translated from animal experiments, we hypothesize that activation of the VDR represents a method to lower renal-vascular tissue-RAS activity in human diabetes, and could therefore play an important role in the primary prevention of diabetic nephropathy. We therefore designed the VALIDATE-D study: an ongoing randomized, double-blinded, placebo-controlled study to assess whether direct VDR activation: Aim 1) lowers circulating RAS activity in human diabetes; Aim 2) lowers renal-vascular tissue-RAS activity in human diabetes; and Aim 3) in combination with ACE inhibition, exerts an additive or synergistic effect on the renal-vascular tissue-RAS and proteinuria.

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