Characterizing the Impact of Vitamin D and High Dietary Phosphate on Parathyroid Gland Structure and Function in Chronic Kidney Disease
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Authors
Khan, Sono
Date
Type
thesis
Language
eng
Keyword
parathyroid gland , chronic kidney disease , immunohistochemistry , megalin , vitamin D , 1,25(OH)2D3 , 25(OH)D3 , CaSR , CellProfiler , parathyroid hyperplasia , parathyroid hypertrophy , secondary hyperparathyroidism
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Abstract
Chronic kidney disease (CKD) affects around 40 million North Americans and significantly contributes to global cardiovascular disease and mortality. CKD-induced systemic dysregulation of phosphate metabolism promotes secondary hyperparathyroidism (SHPT), in which pathological parathyroid gland (PTG) calcium-sensing receptor (CaSR)-based signalling plays a significant role. Clinical interventions such as vitamin D-based treatments aim to control hypersecreting parathyroid hormone (PTH), producing significant maladaptive effects. However, PTG phenotypes of vitamin D resistance and mineral insensitivity arise in SHPT, lessening the efficacy of these interventions. This study aimed to investigate how calcitriol (active vitamin D) and calcifediol, the precursor to calcitriol, affect the structure and cellularity of the PTG. In addition, to elucidate the CKD time course and role of high dietary phosphate on PTG pathogenesis. In two experiments, a 9-week dietary adenine-induced CKD rat model was employed to determine: (i) the effect of calcitriol and calcifediol treatment on CKD rats; and (ii) the time course of changes in CKD animals at 4 and 7 weeks of low dietary phosphate (0.5%) and at week 9 of CKD induction, but after two weeks of high dietary phosphate (1%). In addition to standard biochemical assessments, CaSR immunohistochemistry was performed on PTGs to visualize changes in the glandular phenotypes. A CellProfiler-based image analysis protocol was developed to quantify parathyroid cellularity and structure. Novel CKD-induced parathyroid tissue phenotypes were identified, including cell hypertrophy, reductions in connective tissue, and the presence of skewed basolateral CaSR expression exclusively adjacent to connective tissue. Cell size quantification indicated a dramatic CKD-induced hypertrophic effect on parathyroid cell size (1.72-fold, p<0.0001), exacerbated by calcitriol (1.84-fold, p<0.0001) and protected against by calcifediol (1.54-fold, p<0.0001). CKD induced a significant increase in parathyroid cell number (1.59-fold, p<0.0001), with proliferation preceding hypertrophy from four weeks into CKD pathogenesis. PTG cellularity measurements correlated strongly with PTH, fibroblast growth factor-23 (FGF-23), phosphate, and creatinine. Overall, our findings demonstrate significant CKD-induced pathological alterations to parathyroid cellularity and morphology. The calcitriol-induced stimulation of hypertrophy suggests it is not an ideal therapy, whereas the lesser calcifediol impact, compared to calcitriol, was promising. Lastly, the emerging relevance of the endocytic receptor megalin is reviewed.
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Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
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Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivs 3.0 United States
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivs 3.0 United States