title: Let-7andMicroRNA-148Regulate Parathyroid Hormone Levels in Secondary Hyperparathyroidism.
abstract: Secondary hyperparathyroidism commonly complicates CKD and associates with morbidity and mortality. We profiled microRNA (miRNA) in parathyroid glands from experimental hyperparathyroidism models and patients receiving dialysis and studied the function of specific miRNAs. miRNA deep-sequencing showed that human and rodent parathyroids share similar profiles. Parathyroids from uremic and normal rats segregated on the basis of their miRNA expression profiles, and a similar finding was observed in humans. We identified parathyroid miRNAs that were dysregulated in experimental hyperparathyroidism, including miR-29, miR-21, miR-148, miR-30, and miR-141 (upregulated); and miR-10, miR-125, and miR-25 (downregulated). Inhibition of the abundant let-7 family increased parathyroid hormone (PTH) secretion in normal and uremic rats, as well as in mouse parathyroid organ cultures. Conversely, inhibition of the upregulated miR-148 family prevented the increase in serum PTH level in uremic rats and decreased levels of secreted PTH in parathyroid cultures. The evolutionary conservation of abundant miRNAs in normal parathyroid glands and the regulation of these miRNAs in secondary hyperparathyroidism indicates their importance for parathyroid function and the development of hyperparathyroidism. Specifically, let-7 and miR-148 antagonism modified PTH secretionin vivoandin vitro, implying roles for these specific miRNAs. These findings may be utilized for therapeutic interventions aimed at altering PTH expression in diseases such as osteoporosis and secondary hyperparathyroidism.
authors.affiliation: Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and.
authors.forename: Vitali
authors.initials: V
authors.lastname: Shilo
authors.affiliation: Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and.
authors.forename: Irit
authors.initials: I
authors.lastname: Mor-Yosef Levi
authors.affiliation: Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and.
authors.forename: Roy
authors.initials: R
authors.lastname: Abel
authors.affiliation: Johns Hopkins Wilmer Eye Institute, Baltimore, Maryland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mihailović
authors.affiliation: Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and.
authors.forename: Gilad
authors.initials: G
authors.lastname: Wasserman
authors.affiliation: Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and.
authors.forename: Tally
authors.initials: T
authors.lastname: Naveh-Many
authors.affiliation: Nephrology and Hypertension, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and iddo@hadassah.org.il.
authors.forename: Iddo Z
authors.initials: IZ
authors.lastname: Ben-Dov
mesh_terms: D000818:Animals; D006962:Hyperparathyroidism, Secondary / Q000097:blood* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D010281:Parathyroid Hormone / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; C554644:Mirn148 microRNA, mouse; D010281:Parathyroid Hormone; C583909:mirnlet7e microRNA, mouse
keywords: chronic kidney disease; gene expression; hyperparathyroidism; microRNA; mineral metabolism