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Secondary hyperparathyroidism (SHP) associated with chronic kidney disease (CKD) represents a significant health concern, contributing to morbidity and mortality. Despite its clinical importance, the underlying causes of CKD-SHP and the related parathyroid signaling pathways remain elusive. Our previous research demonstrated the activation of the parathyroid mTORC1 pathway in CKD-SHP. Utilizing novel genetically modified mouse models and clinical data from 106 healthcare organizations, we reveal intricate connections between mTORC1 activity, parathyroid gland structure, and the response to CKD.
We generated mice with parathyroid (PT) specific mTORC1 deficiency (PT-mTORC1-/-) or tuberous sclerosis complex 1 (Tsc1) deficiency (PT-Tsc1-/-) combined with tdTomato expression to identify the parathyroid glands by fluorescent microscopy. Mice were fed an adenine high phosphorus diet or injected with folic acid to induce CKD or AKI respectively. Parathyroid glands in organ culture were incubated with different calcium concentrations. Data from human kidney transplant recipients undergoing immunosuppressive treatment regimens of mTOR inhibitors or calcineurin inhibitors was collected from the TriNetX network datasets 22 comprising over 127 million individuals, representing data derived from 106 healthcare organizations.
Surprisingly, PT-mTORC1 mice exhibited disrupted parathyroid glands, replaced by scattered clumps of parathyroid cells from early after birth, compared to the intact glands in PT-mTORC1+/+ control littermates. Despite absence of intact glands, these mice had normal basal serum PTH levels, which increased to levels similar to controls upon dietary-induced CKD. However, PT-mTORC1-/- failed to increase serum PTH in response to folic acid induced acute kidney injury (AKI), highlighting the adaptability of the parathyroids to chronic but not acute stimulation. In contrast, PT-Tsc1-/- mice, characterized by hyperactivation of mTORC1, had enlarged glands and elevated basal serum PTH and calcium levels. PT-Tsc1-/- mice exhibited a CKD-induced rise in serum PTH comparable to control PT-Tsc1+/+ littermates, albeit with a reduced magnitude increase, suggesting compromised secretion capacity in CKD PT-Tsc1-/- mice. Parathyroid glands from PT-Tsc1-/- mice in culture displayed sustained high PTH secretion into the growth medium, which did not further increase when exposed to low-calcium media, unlike glands from control mice. Clinical data collected from kidney transplant recipients demonstrated that drug-induced mTOR inhibition is associated with reduced serum PTH levels, suggesting a central role for mTORC1 in SHP-CKD.
Collectively our findings highlight the essential roles of mTORC1 in maintaining postnatal parathyroid gland integrity and in the pathogenesis of CKD-induced SHP. These findings contribute to a better understanding of the complex regulatory mechanisms involved in SHP pathogenesis. They offer new avenues for understanding and identifying novel therapeutic targets for parathyroid-related disorders.