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. 2025 Nov 25.
doi: 10.1681/ASN.0000000942. Online ahead of print.

A Ciliary Phosphoinositide Pathway Regulates the Dosage of Polycystins in Primary Cilia

Chuan Chen  1   2 , Zhifei Wang  3 , Yue Gao  1   2 , Madilyn R Ellis  1 , Biyun Ji  1   2 , Cynthia J Sieben  2 , Courtney J Haycraft  4 , Mandy Croyle  4 , Ariana Aghevli  1 , Qingwen Xu  1 , Jielu H Robichaud  1   2 , Kai He  1   2 , Chunhua Chen  1 , Yan Huang  1   2 , Bradley K Yoder  4 , Jinghua Hu  1   2 , Peter C Harris  1   2 , Yong Yu  3 , Kun Ling  1   2
Affiliations

A Ciliary Phosphoinositide Pathway Regulates the Dosage of Polycystins in Primary Cilia

Chuan Chen et al. J Am Soc Nephrol. .

Abstract

Key points: Inositol polyphosphate-5-phosphatase E (INPP5E) and type Ig phosphatidylinositol-4-phosphate 5-kinase (PIPKIγ) coordinated the homeostasis of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate in primary cilia. Modulating INPP5E or PIPKIγ activity changed the level of polycystin-1 and polycystin-2 in primary cilia. INPP5E inhibition increased the hypomorphic PKD1 variants (PC1-R3277C) in cilia and reduced cystogenesis in the kidney in vitro .

Background: Autosomal dominant polycystic kidney disease is mainly caused by mutations in PKD1 and PKD2 , which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 assemble a cation channel complex enriched in primary cilium, a sensory organelle associated with various developmental diseases, including polycystic kidney disease (PKD). Accumulating evidence supports the necessity of functional polycystin (PC) complex in cilia to prevent cystogenesis in the kidney, indicating that improving their ciliary levels may ameliorate defects underlying PKD pathogenesis. Yet, molecular mechanisms underlying the ciliary targeting and homeostasis of the PC complex are not fully understood.

Methods: Indirect immunofluorescence microscopy was used to monitor ciliary levels of PC1 and PC2 in renal epithelial cells. Electrophysiology analysis in oocytes was used to determine the channel activity of the PC complex. Cystogenesis in the kidney was measured using in vitro 3D-Matrigel cell models and ex vivo mouse embryonic kidney models.

Results: Suppressing inositol polyphosphate-5-phosphatase E (INPP5E) or activating type Ig phosphatidylinositol-4-phosphate 5-kinase raised ciliary levels of the PC complex in both normal renal epithelial cells and cells carrying autosomal dominant polycystic kidney disease mutations that interrupt the trafficking of PCs into cilia, including GANAB inactivation and the trafficking PKD1 mutation p.Arg3277Cys (RC). PC1 RC formed a complex with PC2 and exhibited normal channel activity in vitro . An INPP5E that increases PC1 and PC2 in cilia, suppressed in vitro forskolin-induced cystogenesis of inner medullary collecting duct epithelial cell line 3 cells in 3D Matrigel and ex vivo cyst formation in embryonic Pkd1RC/RC mouse kidneys.

Conclusions: Our results demonstrated that increasing the ciliary level of PCs, by manipulating a ciliary phosphoinositide signaling axis, enhanced the functionality of PCs and suppressed cystogenesis of renal epithelial cells in vitro .

Keywords: ADPKD; cell biology and structure; cystic kidney disease; polycystic kidney disease.

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References

    1. Dalgaard OZ. Bilateral polycystic disease of the kidneys; a follow-up of two hundred and eighty-four patients and their families. Acta Med Scand Suppl. 1957;328:1–255. PMID: 13469269.
    1. Iglesias CG, Torres VE, Offord KP, Holley KE, Beard CM, Kurland LT. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935–1980. Am J Kidney Dis. 1983;2(6):630–639. doi: 10.1016/s0272-6386(83)80044-4 - DOI
    1. Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM, Torres VE. Polycystic kidney disease. Nat Rev Dis Primers. 2018;4(1):50. doi: 10.1038/s41572-018-0047-y - DOI
    1. Ong AC, Harris PC. A polycystin-centric view of cyst formation and disease: the polycystins revisited. Kidney Int. 2015;88(4):699–710. doi: 10.1038/ki.2015.207 - DOI
    1. Hughes J, Ward CJ, Peral B, et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet. 1995;10(2):151–160. doi: 10.1038/ng0695-151 - DOI

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