Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease

Naveh-Many, Tally; Volovelsky, Oded

doi:10.3390/ijms21124332

Cited by 24 publications

(20 citation statements)

References 112 publications

(136 reference statements)

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“…These results highlight the essential role of mTORC1 activation by rpS6 phosphorylation in parathyroid cell proliferation and in the pathogenesis of SHP. EGFR activates the AKT-mTORC1 pathway; therefore, the mTORC1 and EGFR pathways may act together to stimulate parathyroid cell proliferation in SHP [99] (Figure 3).…”

Section: The Mtorc1 Pathwaymentioning

confidence: 99%

Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease

et al. 2022

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Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the increased PTH gene expression is post-transcriptional and mediated by PTH mRNA–protein interactions that promote PTH mRNA stability. These interactions are orchestrated by the isomerase Pin1. Pin1 participates in conformational change-based regulation of target proteins, including mRNA-binding proteins. In SHP, Pin1 isomerase activity is decreased, and thus, the Pin1 target and PTH mRNA destabilizing protein KSRP fails to bind PTH mRNA, increasing PTH mRNA stability and levels. An additional level of post-transcriptional regulation is mediated by microRNA (miRNA). Mice with parathyroid-specific knockout of Dicer, which facilitates the final step in miRNA maturation, lack parathyroid miRNAs but have normal PTH and calcium levels. Surprisingly, these mice fail to increase serum PTH in response to hypocalcemia or uremia, indicating a role for miRNAs in parathyroid stimulation. SHP often leads to parathyroid hyperplasia. Reduced expressions of parathyroid regulating receptors, activation of transforming growth factor α-epidermal growth factor receptor, cyclooxygenase 2-prostaglandin E2 and mTOR signaling all contribute to the enhanced parathyroid cell proliferation. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. This review summarizes the current knowledge on the mechanisms that stimulate the parathyroid cell at multiple levels in SHP.

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Section: The Mtorc1 Pathwaymentioning

confidence: 99%

Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease

et al. 2022

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“…Several epidemiological studies report an association between plasma phosphate and increased cardiovascular disease and mortality in dialysis and pre-dialysis CKD population as well as in the general population [56][57][58][59][60][61]. The observational studies are also backed up by experimental studies illustrating a negative impact on the organism by phosphate overload [62][63][64][65][66][67]. More specifically, Li et al showed in in vitro studies that extracellular phosphate uptake via the type III sodium phosphate co-transporter (Pit1) induced the change in the phenotype of VSMC to a bone-like cell.…”

Section: Dramatic Changes In the Vasculature In Ckdmentioning

confidence: 99%

New Insights to the Crosstalk between Vascular and Bone Tissue in Chronic Kidney Disease–Mineral and Bone Disorder

et al. 2021

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Vasculature plays a key role in bone development and the maintenance of bone tissue throughout life. The two organ systems are not only linked in normal physiology, but also in pathophysiological conditions. The chronic kidney disease–mineral and bone disorder (CKD-MBD) is still the most serious complication to CKD, resulting in increased morbidity and mortality. Current treatment therapies aimed at the phosphate retention and parathyroid hormone disturbances fail to reduce the high cardiovascular mortality in CKD patients, underlining the importance of other factors in the complex syndrome. This review will focus on vascular disease and its interplay with bone disorders in CKD. It will present the very late data showing a direct effect of vascular calcification on bone metabolism, indicating a vascular-bone tissue crosstalk in CKD. The calcified vasculature not only suffers from the systemic effects of CKD but seems to be an active player in the CKD-MBD syndrome impairing bone metabolism and might be a novel target for treatment and prevention.

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“…Furthermore, the binding of vitamin D to VDR of the parathyroid gland inhibits PTH synthesis, which constitutes an important feedback mechanism related to Ca 2+ homeostasis ( Navarro-García et al, 2018 ). The loss of renal function is frequently related to vitamin D deficiency ( Wolf, 2010 ) and increased synthesis of PTH (secondary hyperparathyroidism) ( Madsen et al, 1981 ; Naveh-Many and Volovelsky, 2020 ).…”

Section: Mineral Bone Disorders and Cardiorenal Syndromementioning

confidence: 99%

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets

et al. 2021

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Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.

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Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease

Cited by 24 publications

References 112 publications

Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease

Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease

New Insights to the Crosstalk between Vascular and Bone Tissue in Chronic Kidney Disease–Mineral and Bone Disorder

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets

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