Abstract: TH-PO145
CKD Alters Parathyroid Pin1 Phosphorylation and Hence PTH mRNA Binding Proteins Leading to Secondary Hyperparathyroidism
Session Information
- CKD-MBD: Targets and Outcomes
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Hassan, Alia, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
- Nechama, Morris, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
- Silver, Justin, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
- Ben-Dov, Iddo Z., Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
- Naveh-Many, Tally, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
Background
Secondary hyperparathyroidism (SHP) is a common complication of CKD that increases morbidity and mortality. In experimental models of CKD and SHP, the increased PTH gene expression is due to enhanced PTH mRNA stability, mediated by changes in PTH mRNA interaction with stabilizing AUF1 and destabilizing KSRP. The isomerase Pin1 leads to KSRP dephosphorylation, but in SHP, parathyroid Pin1 activity is decreased and hence phosphorylated KSRP fails to bind PTH mRNA resulting in high PTH mRNA stability and levels. Here we aim to identify the up- and down-stream mechanisms by which CKD stimulates the parathyroid in SHP.
Methods
CKD and SHP were induced in rats and mice by adenine-rich high phosphorus diets. Parathyroid organ cultures and transfected cells were incubated with Pin1 inhibitors for their effect on PTH expression. Mass-spectrometry was performed on both parathyroid and PTH mRNA pulled down proteins.
Results
We characterized, for the first time, the global changes in protein expression and phosphorylation induced by kidney failure in the minute rat parathyroid glands. CKD led to changes in rat parathyroid proteome and phosphoproteome profiles, including KSRP phosphorylation at Pin1 target sites. Furthermore, both acute and chronic kidney failure led to parathyroid-specific Pin1 Ser16 and Ser71 phosphorylation, which disrupts Pin1 activity. Pharmacologic Pin1 inhibition, that mimics the decreased Pin1 activity in SHP, increased PTH expression ex-vivo in parathyroid glands in culture and in transfected cells, through the PTH mRNA protein-interacting element and KSRP phosphorylation. We also characterized the effect of Pin1 inhibition on global PTH mRNA interacting proteins.
Conclusion
Kidney failure leads to loss of parathyroid Pin1 activity by inducing Pin1 phosphorylation. This predisposes parathyroids to increase PTH production through impaired PTH mRNA decay that is dependent on KSRP phosphorylation at Pin1-target motifs. Pin1 and KSRP phosphorylation and the Pin1-KSRP-PTH mRNA axis thus drive SHP.