Dicer-Mediated mTORC1 Signaling and Parathyroid Gland Integrity and Function.

Abstract

Secondary hyperparathyroidism of CKD contributes significantly to patient morbidity and mortality. The underlining mechanisms of CKD-induced secondary hyperparathyroidism remain elusive. We previously demonstrated that PT-Dicer-/- mice, with parathyroid specific deletion of the miRNA processing enzyme Dicer and consequently miRNA maintain normal basal serum PTH levels but do not develop secondary hyperparathyroidism induced by CKD. Additionally, we showed that the parathyroid mTORC1 pathway is activated in CKD. We now explored the roles of Dicer/miRNA and mTORC1 in parathyroid development and function. We generated mice with parathyroid specific Dicer (PT-Dicer-/-), mTOR (PT-mTOR-/-) or tuberous sclerosis complex 1 (PT-Tsc1-/-) deficiency combined with YFP or tdTomato expression, to identify the parathyroids by fluorescent microscopy. CKD was induced by an adenine-rich high phosphate diet. Despite normal basal serum PTH levels, PT-Dicer-/- mice displayed apoptotic loss of intact parathyroid glands postnatally, and reduced mTOR activity. PT-mTOR-/- mice lacked intact parathyroid glands, yet maintained normal serum PTH levels, mirroring the phenotype of PT-Dicer-/- mice. Conversely, PT-Tsc1-/- mice with hyperactivated mTORC1, exhibited enlarged glands along with elevated basal serum PTH and calcium levels. Significantly, PT-Dicer-/-;Tsc1-/- double knockout mice, preserved intact parathyroid glands and reinstated CKD-induced secondary hyperparathyroidism. mTORC1 operates downstream of Dicer and miRNA in the parathyroid and is essential for maintaining postnatal parathyroid gland integrity throughout life and for the pathogenesis of CKD-induced secondary hyperparathyroidism.