MiR-129 Blocks Secondary Hyperparathyroidism-Inducing Fgf23/αKlotho Signaling in Mice with Chronic Kidney Disease

Abstract

BackgroundSecondary hyperparathyroidism, a condition of excess parathyroid hormone (PTH, Pth) production, is often seen in chronic kidney disease (CKD) patients with elevated fibroblast growth factor 23 (FGF23, Fgf23). Elevated FGF23 levels stimulate secondary hyperparathyroidism-associated parathyroid αKlotho signaling. As overexpression of rationally selected microRNAs can suppress target gene activation, we hypothesized that microRNA-based suppression of parathyroid FGF23/αKlotho axis activity may be a potential strategy to combat secondary hyperparathyroidism. MethodsIn vitro luciferase assays and human parathyroid adenoma cell experiments were used to determine miR-129-1-3p's effects on αKlotho expression in vitro. We also studied the effects of parathyroid-specific miR-129-1 overexpression (miR-129Ox) in CKD and non-CKD mice and parathyroid tissue cultures derived therefrom. ResultsmiR-129-1-3p directly targets the αKlotho mRNA strand in human parathyroid cells. miR-129Ox CKD mice and control CKD mice displayed comparable serum levels of calcium, phosphate, Fgf23, and 1,25-dihydroxyvitamin D (1,25(OH)2D). However, miR-129Ox CKD mice displayed reduced parathyroid αKlotho expression and lower circulating Pth levels. In vitro culture of miR-129Ox CKD murine parathyroid tissue showed suppressed responses to Fgf23, with decreased Pth secretion and diminished cell proliferation after four days. ConclusionsmiR-129 negatively regulates pro-proliferative, Pth-inducing Fgf23/α​Klotho signaling in the parathyroid glands of CKD mice.