Cross Talk Between the Renin-Angiotensin-Aldosterone System and Vitamin D-FGF-23-klotho in Chronic Kidney Disease

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in renal progression and its complications. Accordingly, RAAS blockade has been the cornerstone of renoprotective interventions. Vitamin D deficiency is traditionally recognized as a key factor in the bone and mineral disturbances of chronic kidney disease (CKD), and vitamin D supplementation is standard treatment for many renal patients. As reviewed elsewhere, 1 vitamin D interacts with the more recently identified moieties, fibroblast growth factor 23 (FGF-23) and klotho. As such, vitamin D, FGF-23, and klotho represent an endocrine axis involved in the regulation of calcium and phosphate metabolism.Besides having effects on mineral metabolism, vitamin D deficiency is also associated with progressive renal disease and with mortality in chronic kidney disease (CKD). 2,3 In line with these observations, the use of vitamin D analogues may provide with a survival advantage in dialysis patients, 4 Recent studies show that angiotensin II reduces renal expression of klotho, which, in turn, modulates FGF-23-signaling and 1-alpha hydroxylase, the enzyme converting calcidiol to calcitriol. As derangement of the vitamin D-FGF-23-klotho axis associates with cardiovascular complications in several studies, the interactions of this axis with the RAAS may have therapeutic implications in CKD patients, regarding both renal and cardiovascular outcomes. MODULATION OF THE RAAS BY VITAMIN DThe first clinical studies suggesting an inverse relationship between calcitriol and renin levels were published two decades ago 9,10 and were recently confirmed in a large cohort study. 11 Vitamin D deficiency, defined as calcidiol levels below 15 ng/ml, associates with reduced renal plasma flow responses to infused angiotensin II, suggesting endogenous intrarenal RAAS activation in vitamin D deficient subjects, 12 and intervention with calcitriol decreases plasma renin and angiotensin II levels in hemodialysis patients with secondary hyperparathyroidism. 13 Published online ahead of print. Publication date available at www.jasn.org. ABSTRACTThere is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an...

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“…Conversely, administration of exogenous soluble klotho may offer cardiovascular‐renal protection in chronic kidney disease by blunting the activation of RAS 45. A bidirectional link between klotho and RAS has been described and confirmed by previous work from our group 46, 47.…”

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“…Impairment of endothelial function, which accompanies CKD,2 is recognized as a sentinel event in the development and progression of cardiovascular disease 3. As kidney function declines, there is a progressive decline of both plasma 25 hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH) 2 D) concentrations, and of the kidney‐derived protein α‐Klotho, accompanied by secondary hyperparathyroidism and increased fibroblast growth factor‐23 levels 4, 5. These hormonal disturbances occur already in early‐stage CKD and are proposed to a make a notable contribution to the initiation and progression of cardiovascular disease 6, 7.…”

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“…Vitamin D is a well-recognized regulator of endothelial function and moreover it was found to stimulate the production of renin in the kidney and consequently to lead in increased angiotensin II levels [54,55]. Thus, it is plausible Fibroblast growth Factor-23: a novel biomarker For cardiovascular disease ... that some of the effects of FGF-23 on the cardiovascular system are at least partly mediated through suppression on active vitamin D. Moreover, FGF-23 may also induce endothelial dysfunction by directly interfering with nitric oxide (NO)-mediated vasodilation.…”