Kidney Failure Alters Parathyroid Pin1 Phosphorylation and Parathyroid Hormone mRNA-Binding Proteins, Leading to Secondary Hyperparathyroidism

Abstract

BackgroundSecondary hyperparathyroidism (SHP) is a common complication of CKD that increases morbidity and mortality. In experimental SHP, increased parathyroid hormone (PTH) expression is due to enhanced PTH mRNA stability, mediated by changes in its 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. The up- and downstream mechanisms by which CKD stimulates the parathyroid glands remain elusive.MethodsAdenine-rich high-phosphate diets induced CKD in rats and mice. 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.ResultsCKD 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, which 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 interaction element and KSRP phosphorylation.ConclusionsKidney 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.

Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid–Induced AKI

“…Twenty-four hours after FA-AKI induction, plasma PTH increased in the NP-FA group, in line with previous studies, which was abrogated in the LP-FA group (Figure 3A). 41,54,55 Similarly, plasma calcitriol was increased in the NP-FA group compared with the LP-FA group, which was paralleled by higher renal Cyp27b1 mRNA expression. Renal Cyp24a1 mRNA was downregulated in the NP-FA but not the LP-FA group (Figure 3, B-D).…”

The molecular mechanisms of peptidyl-prolyl cis/trans isomerase Pin1 and its relevance to kidney disease

“…They found that Pin1 is expressed in ureteric bud derivatives and mediates the function of protein kinase-X (PRKX), a regulator of epithelial morphogenesis, through the WW domain of Pin1 ( Li et al, 2009 ). In contrast, Pin1 has been linked to the occurrence and progression of various kidney diseases ( Thorpe et al, 2001 ; Hassan et al, 2022a ; Patel et al, 2022 ). Genetic or pharmacological inhibition of Pin1 may help reduce renal injury by mitigating kidney fibrosis, oxidative stress, and apoptosis ( Shen et al, 2016 ; Zhao et al, 2021 ).…”

“…In CKD, Pin1 isomerization becomes inactive, leading to reduced Pin1-mediated dephosphorylation and conformational changes of K-homology splicing regulatory protein (KSRP). Consequently, KSRP fails to effectively bind to PTH mRNA ( Kilav-Levin et al, 2020 ; Hassan et al, 2022a ; Hassan et al, 2022b ). This results in decreased PTH mRNA destabilization by KSRP, whereas stabilization by adenosine-uridine-rich binding factor 1 (AUF1) increases, leading to elevated PTH mRNA levels and stability ( Kilav-Levin et al, 2020 ) ( Figure 6 ).…”

The essential roles of Dicer-mediated mTORC1 signaling in parathyroid gland integrity and function: Insights from genetic mouse models and clinical data

“…Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with patient morbidity and mortality (1,2). In experimental SHP, the increase in PTH gene expression is attributed to posttranscriptional mechanisms due to enhanced PTH mRNA stability (3)(4)(5). An additional layer of post-transcriptional control is mediated by microRNA (miRNA).…”