TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium
Abstract Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca2+]i homeostasis and flow‐sensitive [Ca2+]i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP‐dependent fluid secretion along with deficient mechanosensitivit...
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.15641 |
| _version_ | 1797375099434696704 |
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| author | Kyrylo Pyrshev Anna Stavniichuk Viktor N. Tomilin Naghmeh Hassanzadeh Khayyat Guohui Ren Mariya Kordysh Oleg Zaika Mykola Mamenko Oleh Pochynyuk |
| author_facet | Kyrylo Pyrshev Anna Stavniichuk Viktor N. Tomilin Naghmeh Hassanzadeh Khayyat Guohui Ren Mariya Kordysh Oleg Zaika Mykola Mamenko Oleh Pochynyuk |
| author_sort | Kyrylo Pyrshev |
| collection | DOAJ |
| description | Abstract Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca2+]i homeostasis and flow‐sensitive [Ca2+]i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP‐dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K+ intake modulates the rate of cystogenesis and mechanosensitive [Ca2+]i signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD). One month treatment with both high KCl (5% K+) and KB/C (5% K+ with bicarbonate/citrate) diets significantly increased TRPV4 levels when compared to control (0.9% K+). High KCl diet caused an increased TRPV4‐dependent Ca2+ influx, and partial restoration of mechanosensitivity in freshly isolated monolayers of cystic cells. Unexpectedly, high KB/C diet induced an opposite effect by reducing TRPV4 activity and worsening [Ca2+]i homeostasis. Importantly, high KCl diet decreased cAMP, whereas high KB/C diet further increased cAMP levels in cystic cells (assessed as AQP2 distribution). At the systemic level, high KCl diet fed PCK453 rats had significantly lower kidney‐to‐bodyweight ratio and reduced cystic area. These beneficial effects were negated by a concomitant administration of an orally active TRPV4 antagonist, GSK2193874, resulting in greater kidney weight, accelerated cystogenesis, and augmented renal injury. High KB/C diet also exacerbated renal manifestations of ARPKD, consistent with deficient TRPV4 activity in cystic cells. Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression. |
| first_indexed | 2024-03-08T19:17:19Z |
| format | Article |
| id | doaj.art-3b29b6251de64c85af74876f3675b2e4 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-08T19:17:19Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-3b29b6251de64c85af74876f3675b2e42023-12-27T04:12:43ZengWileyPhysiological Reports2051-817X2023-03-01116n/an/a10.14814/phy2.15641TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassiumKyrylo Pyrshev0Anna Stavniichuk1Viktor N. Tomilin2Naghmeh Hassanzadeh Khayyat3Guohui Ren4Mariya Kordysh5Oleg Zaika6Mykola Mamenko7Oleh Pochynyuk8Department of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USADepartment of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USADepartment of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USADepartment of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USADepartment of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USADepartment of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USADepartment of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USADepartment of Physiology Augusta University Augusta Georgia USADepartment of Integrative Biology and Pharmacology The University of Texas Health Science Center at Houston Houston Texas USAAbstract Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca2+]i homeostasis and flow‐sensitive [Ca2+]i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP‐dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K+ intake modulates the rate of cystogenesis and mechanosensitive [Ca2+]i signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD). One month treatment with both high KCl (5% K+) and KB/C (5% K+ with bicarbonate/citrate) diets significantly increased TRPV4 levels when compared to control (0.9% K+). High KCl diet caused an increased TRPV4‐dependent Ca2+ influx, and partial restoration of mechanosensitivity in freshly isolated monolayers of cystic cells. Unexpectedly, high KB/C diet induced an opposite effect by reducing TRPV4 activity and worsening [Ca2+]i homeostasis. Importantly, high KCl diet decreased cAMP, whereas high KB/C diet further increased cAMP levels in cystic cells (assessed as AQP2 distribution). At the systemic level, high KCl diet fed PCK453 rats had significantly lower kidney‐to‐bodyweight ratio and reduced cystic area. These beneficial effects were negated by a concomitant administration of an orally active TRPV4 antagonist, GSK2193874, resulting in greater kidney weight, accelerated cystogenesis, and augmented renal injury. High KB/C diet also exacerbated renal manifestations of ARPKD, consistent with deficient TRPV4 activity in cystic cells. Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression.https://doi.org/10.14814/phy2.15641[Ca2+]i signalingcAMPmechanosensitivityPCK453 ratsrenal injury |
| spellingShingle | Kyrylo Pyrshev Anna Stavniichuk Viktor N. Tomilin Naghmeh Hassanzadeh Khayyat Guohui Ren Mariya Kordysh Oleg Zaika Mykola Mamenko Oleh Pochynyuk TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium Physiological Reports [Ca2+]i signaling cAMP mechanosensitivity PCK453 rats renal injury |
| title | TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium |
| title_full | TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium |
| title_fullStr | TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium |
| title_full_unstemmed | TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium |
| title_short | TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium |
| title_sort | trpv4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium |
| topic | [Ca2+]i signaling cAMP mechanosensitivity PCK453 rats renal injury |
| url | https://doi.org/10.14814/phy2.15641 |
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