Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality.
In the course of kidney disease, the progressive loss of renal capacity to maintain normal serum levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) is a main contributor to parathyroid hyperplasia and high serum PTH. High PTH causes mineral and skeletal abnormalities predisposing to ectopic calcifications and increased mortality. Intriguingly, replacement therapy with 1,25(OH)2D or its less calcemic analogs was recently shown to improve survival in kidney disease patients through renal and cardiovascular protective actions that are independent of PTH suppression. This work presents preliminary evidence that 1,25(OH)2D inhibition of TACE (Tumor necrosis factor Alpha Converting Enzyme) is a potential common mechanism underlying the efficacy of therapy with 1,25(OH)2D or its analogs to improve outcomes in chronic kidney disease. 1,25(OH)2D prevents/moderates not only the onset and progression of parathyroid TACE/TGFalpha-driven secondary hyperparathyroidism, but, more significantly, renal TACE/TGFalpha-driven fibrotic and inflammatory lesions to the renal parenchyma, and TACE/TNFalpha-driven systemic inflammation, which is known to aggravate renal and cardiovascular lesions and enhance the risk of vascular calcification and cardiovascular mortality.
Dusso
Adriana
A
Renal Division, Washington University School of Medicine, St. Louis, MO 63110, USA. adusso@wustl.edu
Arcidiacono
Maria Vittoria
MV
Yang
Jing
J
Tokumoto
Masanori
M
D051722:ADAM Proteins / Q000097:blood / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000401:mortality*; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000378:metabolism*; D018450:Disease Progression; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D051379:Mice; D008954:Models, Biological; D051381:Rats; D016896:Treatment Outcome; D014807:Vitamin D / Q000378:metabolism*
D015415:Biomarkers; D014807:Vitamin D; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat