Non-Additive Effects of Combined NOX1/4 Inhibition and Calcimimetic Treatment on a Rat Model of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

Autor: Damrath JG; Weldon School of Biomedical Engineering Purdue University West Lafayette IN USA., Chen NX; Division of Nephrology, Department of Medicine Indiana University School of Medicine Indianapolis IN USA., Metzger CE; Department of Anatomy and Cell Biology Indiana University School of Medicine Indianapolis IN USA., Srinivasan S; Division of Nephrology, Department of Medicine Indiana University School of Medicine Indianapolis IN USA., O'Neill K; Division of Nephrology, Department of Medicine Indiana University School of Medicine Indianapolis IN USA., Biruete A; Division of Nephrology, Department of Medicine Indiana University School of Medicine Indianapolis IN USA., Avin KG; Division of Nephrology, Department of Medicine Indiana University School of Medicine Indianapolis IN USA.; Department of Physical Therapy Indiana University School of Health and Rehabilitation Sciences Indianapolis IN USA., Wallace JM; Department of Biomedical Engineering Indiana University-Purdue University at Indianapolis Indianapolis IN USA., Allen MR; Division of Nephrology, Department of Medicine Indiana University School of Medicine Indianapolis IN USA.; Department of Anatomy and Cell Biology Indiana University School of Medicine Indianapolis IN USA., Moe SM; Division of Nephrology, Department of Medicine Indiana University School of Medicine Indianapolis IN USA.; Department of Anatomy and Cell Biology Indiana University School of Medicine Indianapolis IN USA.; Department of Medicine Roudebush Veterans Administration Medical Center Indianapolis IN USA.
Jazyk: angličtina
Zdroj: JBMR plus [JBMR Plus] 2022 Feb 11; Vol. 6 (3), pp. e10600. Date of Electronic Publication: 2022 Feb 11 (Print Publication: 2022).
DOI: 10.1002/jbm4.10600
Abstrakt: Chronic kidney disease-mineral and bone disorder (CKD-MBD) increases cardiovascular calcification and skeletal fragility in part by increasing systemic oxidative stress and disrupting mineral homeostasis through secondary hyperparathyroidism. We hypothesized that treatments to reduce reactive oxygen species formation and reduce parathyroid hormone (PTH) levels would have additive beneficial effects to prevent cardiovascular calcification and deleterious bone architecture and mechanics before end-stage kidney disease. To test this hypothesis, we treated a naturally progressive model of CKD-MBD, the Cy/+ rat, beginning early in CKD with the NADPH oxidase (NOX1/4) inhibitor GKT-137831 (GKT), the preclinical analogue of the calcimimetic etelcalcetide, KP-2326 (KP), and their combination. The results demonstrated that CKD animals had elevated blood urea nitrogen, PTH, fibroblast growth factor 23 (FGF23), and phosphorus. Treatment with KP reduced PTH levels compared with CKD animals, whereas GKT treatment increased C-terminal FGF23 levels without altering intact FGF23. GKT treatment alone reduced aortic calcification and NOX4 expression but did not alter the oxidative stress marker 8-OHdG in the serum or aorta. KP treatment reduced aortic 8-OHdG and inhibited the ability for GKT to reduce aortic calcification. Treatments did not alter heart calcification or left ventricular mass. In the skeleton, CKD animals had reduced trabecular bone volume fraction and trabecular number with increased trabecular spacing that were not improved with either treatment. The cortical bone was not altered by CKD or by treatments at this early stage of CKD. These results suggest that GKT reduces aortic calcification while KP reduces aortic oxidative stress and reduces PTH, but the combination was not additive. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
(© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)
Databáze: MEDLINE
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