Journal of the American Society of Nephrology : JASN · 2026
Parathyroid Hormone Receptor 1 Facilitates Cyst Growth in Genetic Models of Autosomal Dominant Polycystic Kidney Disease.
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Wu Zhaohui, Sun Mengyan, Hu Mingqiang, Yu Qingru, Wang Pan, Luo Lingfei, Ma Ming
Аннотация
KEY POINTS: Parathyroid hormone receptor 1 (Pth1r) localized to renal epithelial primary cilia and underwent parathyroid hormone-induced ciliary trafficking via a conserved valine x proline motif, independent of polycystins. Pth1r inactivation reduced cyst growth, epithelial proliferation, and fibrosis in both developmental and adult-onset autosomal dominant polycystic kidney disease mouse models. Parathyroid hormone activated cAMP signaling, primary cilia enabled efficient cAMP-responsive element-binding phosphorylation, and cinacalcet suppressed parathyroid hormone to slow cyst progression in vivo .
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 , which encode the ciliary proteins polycystin-1 and polycystin-2, respectively. Genetic ablation of primary cilia or disruption of ciliary membrane protein trafficking markedly suppresses cyst formation in adult-onset ADPKD models, indicating that cilia harbor membrane-associated signaling pathways that promote cyst progression. However, the specific ciliary receptors mediating these extracellular cyst promoting signals remain poorly defined.
METHODS: We performed RiboTag-based translational profiling of early cystic kidneys in genetic mouse models of ADPKD to identify differentially expressed genes, with a focus on transmembrane protein-coding candidates. The localization and function of parathyroid hormone receptor 1 (Pth1r) were examined using immunofluorescence, genetic inactivation in developmental and adult-onset ADPKD models, and in vitro studies of renal epithelial cells. Downstream signaling was assessed by cAMP measurements and cAMP-responsive element-binding phosphorylation analysis. Therapeutic relevance was evaluated using the calcimimetic cinacalcet.
RESULTS: RiboTag profiling identified upregulation of Pth1r in early cystic kidneys. Pth1r localized to primary cilia across nephron segments, and its genetic inactivation significantly attenuated cyst growth in both developmental and adult-onset ADPKD models. In vitro , parathyroid hormone (PTH) promoted Pth1r trafficking to cilia through a conserved valine x proline motif independently of polycystins. PTH stimulation increased intracellular cAMP levels in renal epithelial cells, with efficient downstream activation requiring intact primary cilia. In vivo , cAMP-responsive element-binding phosphorylation was increased during cyst progression in Pkd1 -mutant kidneys and was partially reduced by Pth1r inactivation. Cinacalcet treatment reduced cystic burden and normalized circulating PTH levels.
CONCLUSIONS: These findings support a role for Pth1r as a ciliary G protein-coupled receptor linking systemic PTH signaling to cyst-promoting pathways in ADPKD.
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 , which encode the ciliary proteins polycystin-1 and polycystin-2, respectively. Genetic ablation of primary cilia or disruption of ciliary membrane protein trafficking markedly suppresses cyst formation in adult-onset ADPKD models, indicating that cilia harbor membrane-associated signaling pathways that promote cyst progression. However, the specific ciliary receptors mediating these extracellular cyst promoting signals remain poorly defined.
METHODS: We performed RiboTag-based translational profiling of early cystic kidneys in genetic mouse models of ADPKD to identify differentially expressed genes, with a focus on transmembrane protein-coding candidates. The localization and function of parathyroid hormone receptor 1 (Pth1r) were examined using immunofluorescence, genetic inactivation in developmental and adult-onset ADPKD models, and in vitro studies of renal epithelial cells. Downstream signaling was assessed by cAMP measurements and cAMP-responsive element-binding phosphorylation analysis. Therapeutic relevance was evaluated using the calcimimetic cinacalcet.
RESULTS: RiboTag profiling identified upregulation of Pth1r in early cystic kidneys. Pth1r localized to primary cilia across nephron segments, and its genetic inactivation significantly attenuated cyst growth in both developmental and adult-onset ADPKD models. In vitro , parathyroid hormone (PTH) promoted Pth1r trafficking to cilia through a conserved valine x proline motif independently of polycystins. PTH stimulation increased intracellular cAMP levels in renal epithelial cells, with efficient downstream activation requiring intact primary cilia. In vivo , cAMP-responsive element-binding phosphorylation was increased during cyst progression in Pkd1 -mutant kidneys and was partially reduced by Pth1r inactivation. Cinacalcet treatment reduced cystic burden and normalized circulating PTH levels.
CONCLUSIONS: These findings support a role for Pth1r as a ciliary G protein-coupled receptor linking systemic PTH signaling to cyst-promoting pathways in ADPKD.