Hyperosmotic stimuli activate polycystin proteins to aid in urine concentration

Karla M. Márquez-Nogueras; Ryne M. Knutila; Virdjinija Vuchkovska; Charlie Yang; Patricia Outeda; Darren P. Wallace; Ivana Y. Kuo

doi:10.1172/jci.insight.186290

Hyperosmotic stimuli activate polycystin proteins to aid in urine concentration

Karla M. Márquez-Nogueras,¹ Ryne M. Knutila,¹ Virdjinija Vuchkovska,¹ Charlie Yang,² Patricia Outeda,³ Darren P. Wallace,⁴ and Ivana Y. Kuo¹

Published August 5, 2025 - More info

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2) respectively. These proteins are thought to form a signaling complex that can flux cations including calcium. One of the earliest symptoms in ADPKD is a decline in the concentrating ability of the kidneys, occurring prior to cyst formation. We reasoned that hyperosmolality stimulates the polycystin complex, and that the loss of this function impairs water reabsorption. We found that hyperosmolality resulted in the phosphorylation of a microtubule associated protein 4 (MAP4) in a PC1-dependent manner which then elicited ER-localized PC2 calcium signals. ER-localized PC2 hyperosmotic calcium signals were required for trafficking of the water channel aquaporin (AQP2). Pre-cystic PC1-KO and PC2-KO murine kidneys had cytosolic localized AQP2, and diluted urine compared to their respective controls. Kidney tissue sections from ADPKD patients showed decreased AQP2 apical membrane localization in cystic and non-cystic tubules. Our study demonstrates that osmolality is a physiological stimulus of the polycystin complex, and loss of polycystin osmosensing results in impaired water reabsorption via AQP2. This likely contributes to the declined concentrating ability of the kidneys and high circulating vasopressin levels in ADPKD patients.

Hyperosmotic stimuli activate polycystin proteins to aid in urine concentration

Karla M. Márquez-Nogueras,¹ Ryne M. Knutila,¹ Virdjinija Vuchkovska,¹ Charlie Yang,² Patricia Outeda,³ Darren P. Wallace,⁴ and Ivana Y. Kuo¹

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Hyperosmotic stimuli activate polycystin proteins to aid in urine concentration

Karla M. Márquez-Nogueras,1 Ryne M. Knutila,1 Virdjinija Vuchkovska,1 Charlie Yang,2 Patricia Outeda,3 Darren P. Wallace,4 and Ivana Y. Kuo1

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Karla M. Márquez-Nogueras,¹ Ryne M. Knutila,¹ Virdjinija Vuchkovska,¹ Charlie Yang,² Patricia Outeda,³ Darren P. Wallace,⁴ and Ivana Y. Kuo¹