TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease (ARPKD) during variations in dietary potassium

Abstract

Mechanosensitive Ca2+-permeable transient receptor potential vanilloid type 4 (TRPV4) channel plays a dominant role in maintaining intracellular Ca2+ ([Ca2+]i) homeostasis and flow-sensitive [Ca2+]i signaling in the distal segments of renal tubule and collecting duct. Polycystic kidney disease (PKD) manifests as progressive cyst growth with cystic cells exhibiting exacerbated cAMP-dependent fluid secretion along with deficient mechanosensitivity and reduced basal [Ca2+]i levels, and impaired TRPV4 activity. In this study, we tested how regulation of renal TRPV4 function by elevated dietary K+ intake modulates the rate of cystogenesis and mechanosensitive [Ca2+]i signaling in cystic cells of PCK453 rats (1 m.o.), a homologous model of human autosomal recessive PKD (ARPKD), where cyst development is restricted to the collecting duct. One month treatment with both high KCl (5% K+) and KB/C (5% K+ with bicarbonate to citrate in 4:1 ratio) diets significantly increased kidney TRPV4 levels in PCK453 rats when compared to the control group fed regular diet (0.9% K+). High KCl diet also caused an increased TRPV4-dependent Ca2+ influx, higher basal [Ca2+]i, 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 further worsening [Ca2+]i homeostasis. Importantly, high KCl diet decreased, whereas high KB/C diet further increased cAMP levels, as was assessed by the extent of cAMP-dependent translocation of AQP2 water channel to apical membrane in cystic cells. At the systemic level, high KCl diet fed PCK453 rats had significantly lower kidney-to-bodyweight ratio and reduced cystic area in renal sections. The beneficial effects of high KCl diet were negated by a concomitant administration of an orally active TRPV4 antagonist, GSK2193874, resulting in greater kidney weight and accelerated cystogenesis, when compared to these values in control rats. In a similar manner, high KB/C diet exacerbated renal manifestations of ARPKD, consistent with deficient TRPV4 activity in cystic cells. Moreover, KCl+GSK2193874 and high KB/C treated PCK453 rats have increased urinary levels of a renal injury marker, KIM-1.In conclusion, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells upon variations in K+ intake thus attenuating (high activity) or accelerating (low activity) ARPKD progression in PCK453 rats. We propose that pharmacological or dietary means leading to TRPV4 stimulation might be useful to counteract PKD progression in the clinical setting. This research was supported by NIH-NIDDK DK117865, DK119170, AHA EIA35260097 (to O. Pochynyuk) and AHA-19CDA34660148 (to V. N. Tomilin). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.