Kidney Week

Abstract: SA-PO785

Functional TRPV4 Status Sets the Rate of Cytogenesis in Autosomal Recessive Polycystic Kidney Disease (ARPKD) During Variations in Dietary Potassium

Session Information

• Genetic Diseases: Cystic - Genetic Analysis and Extrarenal Manifestations
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Pyrshev, Kyrylo, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, United States

Kyrylo Pyrshev,

• Stavniichuk, Anna, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, United States

Anna Stavniichuk,

• Kordysh, Mariya, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, United States

Mariya Kordysh,

• Zaika, Oleg L., The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, United States

Oleg L. Zaika,

• Pochynyuk, Oleh, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, United States

Oleh Pochynyuk,

Background

Autosomal Recessive Polycystic Kidney Disease (ARPKD) manifests as a progressive growth of the fluid-filled cysts in the collecting duct. Cystic cells are characterized by the impaired intracellular Ca²⁺ signaling ([Ca²⁺]_i), elevated cAMP levels to drive augmented proliferation. Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca²⁺]_i homeostasis and flow-sensitive [Ca²⁺]_i signaling in the collecting duct. Systemic TRPV4 stimulation with GSK1016790A impedes cystogenesis in ARPKD models. Previously, we demonstrated that high dietary K⁺ regimen elevates both activity and expression of renal TRPV4.

Methods

Here, using fluorescence microscopy and systemic measurements, 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 ARPKD rats.

Results

One month treatment with both high KCl (5% K⁺) and KB/C (5% K⁺ with bicarbonate/citrate) diets significantly augmented renal TRPV4 expression in PCK453 rats in comparison to that on the regular diet (0.9% K⁺). We next explored [Ca²⁺]_i levels in freshly isolated renal cysts upon application of TRPV4 agonist GSK1016790A and high flow. Treatment with KCl diet significantly augmented TRPV4-dependent Ca²⁺ influx in cystic cells. Unexpectedly, rats on KB/C intake exhibited diminished elevation of [Ca²⁺]_i concentration in cystic cells in response to both high flow and the agonist comparing to the control. High KCl diet reduced cAMP levels in cystic cells. In contrast, KB/C diet led to the increased cAMP-dependent signaling in cystic cells of ARPKD rats. At the systemic level, high KCl diet significantly decreased kidney-to-bodyweight ratio and reduced the cystic area in kidneys of PCK453 rats. High KB/C diet accelerated ARPKD progression and renal injury leading to a marked increase in the cystic area and particularly the number of cystic dilations in the renal cortex. Of note, application of TRPV4 antagonist GSK2193874 reversed beneficial effects of high KCl diet.

Conclusion

Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression. Augmenting TRPV4 activity by increased dietary K⁺ intake may have therapeutic potential in PKD.

Funding

• NIDDK Support