Kidney Week

Abstract: PO1210

Augmented Renal TRPV4 Activity Attenuates Cystogenesis in ARPKD Rats

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 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, PhD

• Tomilin, Victor N., The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, United States

Victor N. Tomilin,

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

Naghmeh Hassanzadeh Khayyat,

• 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

PKD is characterized by development of cysts in the kidney. Abundant evidence suggested that the impaired mechanosensitivity and disturbed [Ca²⁺]_i homeostasis are the major determinants of the rate of cystogenesis. The rapidly progressing ARPKD is caused by missense mutations in fibrocystin. ARPKD is characterized by the development of cysts almost exclusively in the collecting duct. We have previously demonstrated that mechanosensitive Ca²⁺-permeable TRPV4 channel is preferentially expressed in the collecting duct where its activity is imperative for setting resting [Ca²⁺]_i levels and mediating flow-dependent [Ca²⁺]_i elevations. TRPV4 activity and expression is markedly augmented by high K⁺ intake, known to increase flow in the collecting duct. Thus, we hypothesized that dietary K⁺ supplementation would be beneficial in counteracting cystogenesis during ARPKD by stimulating TRPV4-dependent Ca²⁺ influx.

Methods

We used dietary and pharmacological inputs to establish a correlation between the rate of cystogenesis and TRPV4 function in freshly isolated cyst monolayers in a homologous ARPKD rodent model, PCK453 rats.

Results

We report that treatment of PCK453 rats with high KCl (10%) diet for 1 and 2 months significantly reduced kidney-to-body weight ratio, cystic index, and interstitial fibrosis. We also found a greatly increased total renal TRPV4 expression, channel activity and higher basal [Ca²⁺]_i levels in native cyst cells compared with respective controls. Importantly, the beneficial effects of high KCl diet were abrogated when PCK453 rats were also treated with the selective TRPV4 inhibitor, GSK2193874. GSK2193874 treatment also exacerbated cystogenesis in control PCK453 rats by modestly increasing kidney-to-body weight ratio. Surprisingly, high K⁺ alkali diet (10% KHCO₃/Citrate) also aggravated the disease progression despite augmented renal TRPV4 expression. However, TRPV4-dependent Ca²⁺ fluxes were dramatically suppressed in freshly isolated cyst cell monolayers from high K⁺ alkali fed rats, which is consistent with impaired TRPV4 activity.

Conclusion

Our experiments establish the direct link between TRPV4 function and diminished cystogenesis during ARPKD. We propose that stimulation of TRPV4 by pharmacological or dietary cues could be of clinical relevance to counteract PKD progression.

Funding

• NIDDK Support