TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium.
TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium.
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DOI：
10.14814/phy2.15641
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发表时间：
2023-03
影响因子：
2.5
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中科院分区：
文献类型：
--
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机械敏感性TRPV 4通道在维持肾小管中的[Ca 2 +] i稳态和流动敏感性[Ca 2 +] i信号传导中起主导作用。多囊肾病（PKD）表现为由于cAMP依赖性液体分泌沿着机械敏感性不足和TRPV 4活性受损导致的进行性囊肿生长。在这里，我们测试了通过饮食K+摄入调节肾脏TRPV 4功能如何调节PCK 453大鼠（人类常染色体隐性PKD（ARPKD）的同源模型）囊性细胞中的囊性发生率和机械敏感性[Ca 2 +] i信号传导。与对照组（0.9%K+）相比，高KCl（5%K+）和KB/C（5%K+与碳酸氢盐/柠檬酸盐）饮食治疗一个月后，TRPV 4水平显著增加。高KCl饮食导致TRPV 4依赖性Ca 2+内流增加，并在新鲜分离的单层囊性细胞中部分恢复机械敏感性。出乎意料的是，高KB/C饮食通过降低TRPV 4活性和恶化[Ca 2 +] i稳态诱导相反的效果。重要的是，高KCl饮食降低了cAMP，而高KB/C饮食进一步增加了囊性细胞中的cAMP水平（评估为AQP 2分布）。在全身水平上，喂食高KCl饲料的PCK 453大鼠的肾脏与体重比显着降低，囊性面积减少。这些有益作用被口服活性TRPV 4拮抗剂GSK 2193874的伴随给药所抵消，导致肾脏重量增加、囊肿形成加速和肾损伤加重。高KB/C饮食也加重了ARPKD的肾脏表现，与囊性细胞中TRPV 4活性不足一致。总的来说，我们证明TRPV 4通道活性负调节囊性细胞中的cAMP水平，从而减弱（高活性）或加速（低活性）ARPKD进展。多囊肾（PKD）是一种破坏性的病理学，其特征是大量充满液体的囊肿的发展，导致肾功能下降。先前的证据发现囊状细胞中cAMP水平增加和机械敏感性受损。在这里，我们研究如何机械敏感TRPV 4通道的功能活动影响膀胱生成和cAMP水平在PCK 453大鼠，人类常染色体隐性PKD的同源模型。我们发现，高KCl饮食增加肾脏TRPV 4水平，增加新鲜分离的囊性细胞单层中TRPV 4依赖性Ca 2+内流，并显著减缓PCK 453大鼠肾囊肿的发育和生长。相比之下，囊性细胞中TRPV 4活性受损导致AQP 2水通道的膜积聚，表明囊性细胞中cAMP水平增加，导致大大加速的囊性形成和肾损伤。我们建议，药理学或饮食的手段，导致TRPV 4刺激可能是有用的，以抵消PKD的进展，在临床设置。
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. Polycystic kidney disease (PKD) is a devastating pathology, which is characterized by the development of numerous fluid‐filled cysts leading to declined renal function. Previous evidence found augmented cAMP levels and impaired mechanosensitivity in cystic cells. Here, we investigate how functional activity of the mechanosensitive TRPV4 channel affects cystogenesis and cAMP levels in PCK453 rats, a homologous model of human autosomal recessive PKD. We show that high KCl diet increases renal TRPV4 levels, augments TRPV4‐dependent Ca2+ influx in freshly isolated cystic cell monolayers and markedly slow the development and growth of renal cysts in PCK453 rats. In contrast, impaired TRPV4 activity in cystic cells leads to the membrane accumulation of AQP2 water channel indicative of augmented cAMP levels in cystic cells leading to greatly accelerated cystogenesis and renal injury. We propose that pharmacological or dietary means leading to TRPV4 stimulation might be useful to counteract PKD progression in the clinical setting.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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Walz, Gerd
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作者：
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Pochynyuk OM