Kidney failure alters parathyroid Pin1 phosphorylation and parathyroid hormone mRNA binding proteins leading to secondary hyperparathyroidism

Abstract

Parathyroid hormone (PTH) regulates calcium metabolism and bone strength. Chronic kidney disease (CKD) leads to secondary hyperparathyroidism (SHP) which increases morbidity and mortality. High PTH expression in SHP is due to increased PTH mRNA stability mediated by changes in PTH mRNA interaction with stabilizing AUF1 and destabilizing KSRP. Pin1 isomerizes target proteins, including mRNA binding proteins. In SHP, Pin1 isomerase activity is decreased and phosphorylated KSRP fails to bind PTH mRNA, resulting in high PTH mRNA stability and levels. The molecular mechanisms underlying Pin1 regulation and their effect to increase PTH expression are unknown. We show by mass-spectrometry (MS) the CKD induced changes in rat parathyroid proteome and phosphoproteome profiles. Parathyroid Pin1 Ser16 and Ser71 phosphorylation, that disrupts Pin1 activity, is enhanced in acute and chronic kidney failure rats. Accordingly, pharmacologic Pin1 inhibition increases PTH expression in parathyroid organ cultures and transfected cells, through the PTH mRNA protein binding cis element and KSRP phosphorylation. Therefore, CKD leads to parathyroid loss of Pin1 activity by inducing Pin1 phosphorylation. This predisposes parathyroids to increase PTH production through modified PTH mRNA-KSRP interaction that is dependent on KSRP phosphorylation. CKD induced Pin1 and KSRP phosphorylation and the Pin1-KSRP-PTH mRNA axis thus drive secondary hyperparathyroidism.

Gastrointestinal and renal regulation of calcium metabolism

“…Activated KSRP destabilizes PTH mRNA culminating into its decay or degradation while inactivated KSRP stabilizes PTH mRNA and increases its half-life. miRNA expression regulates PTH gene expression by destabilization of PTH mRNA resulting in PTH mRNA degradation and/or translation repression [50]. Stabilized PTH mRNA undergoes translation in ribosomes, whereas destabilized mRNA are degraded in exosomes.…”

“…The activities of AUF1 and KSRP are regulated by changes in extracellular Ca 2+ and phosphate. Peptidylprolyl cis-trans isomerase NIMA-interacting-1 (Pin1), a peptidyl-prolyl isomerase, alters KSRP phosphorylation and the binding of KSRP to the AREs PTH mRNA [50]. Peptidyl-prolyl cis-trans isomerase NIMA-interacting-1 (Pin1) dephosphorylates inactive KSRP to activated KSRP (figure 8).…”

“…Low serum Ca 2+ and high phosphate levels reduce the activity of Pin1, which induces hyperparathyroidism via inactive KSRP [51]. Regulations in the binding or activity of Pin1 and KSRP are tightly controlled by several post-translational mechanisms some of which are probably mediated by CaSR signaling pathways [50]. Protein kinase A (PKA) and p38 MAPK pathways respectively mediates the phosphorylation of Pin1 and KSRP to impair interactions with their target molecules [50].…”

“…Regulations in the binding or activity of Pin1 and KSRP are tightly controlled by several post-translational mechanisms some of which are probably mediated by CaSR signaling pathways [50]. Protein kinase A (PKA) and p38 MAPK pathways respectively mediates the phosphorylation of Pin1 and KSRP to impair interactions with their target molecules [50]. microRNAs binds PTH genes/mRNAs, as well as CaSR gene and epigenetically regulate their expression in normal and tumorigenic parathyroid cells [52].…”