We have previously shown in renal cells that expression of the water channel Aquaporin-2 increases cell proliferation by a regulatory volume mechanism involving Na⁺/H⁺ exchanger isoform 2. Here, we investigated if Aquaporin-2 (AQP2) also modulates Na⁺/H⁺ exchanger isoform 1-dependent cell proliferation. We use two AQP2-expressing cortical collecting duct models: one constitutive (WT or AQP2-transfected RCCD₁ cell line) and one inducible (control or vasopressin-induced mpkCCD_c14 cell line). We found that Aquaporin-2 modifies Na⁺/H⁺ exchanger isoform 1 (NHE1) contribution to cell proliferation. In Aquaporin-2-expressing cells, Na⁺/H⁺ exchanger isoform 1 is anti-proliferative at physiological pH. In acid media, Na⁺/H⁺ exchanger isoform 1 contribution turned from anti-proliferative to proliferative only in AQP2-expressing cells. We also found that, in AQP2-expressing cells, NHE1-dependent proliferation changes parallel changes in stress fiber levels: at pH 7.4, Na⁺/H⁺ exchanger isoform 1 would favor stress fiber disassembly and, under acidosis, NHE1 would favor stress fiber assembly. Moreover, we found that Na⁺/H⁺ exchanger-dependent effects on proliferation linked to Aquaporin-2 relied on Transient Receptor Potential Subfamily V calcium channel activity. In conclusion, our data show that, in collecting duct cells, the water channel Aquaporin-2 modulates NHE1-dependent cell proliferation. In AQP2-expressing cells, at physiological pH, the Na⁺/H⁺ exchanger isoform 1 function is anti-proliferative and, at acidic pH, Na⁺/H⁺ exchanger isoform 1 function is proliferative. We propose that Na⁺/H⁺ exchanger isoform 1 modulates proliferation through an interplay with stress fiber formation.

中文翻译：

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根据细胞外pH值，表达AQP2的细胞中Na + / H +交换异构体1的活性可能是增生的还是抗增生的

先前我们在肾脏细胞中显示，水通道Aquaporin-2的表达通过涉及Na ⁺ / H ⁺交换异构体2的调节体积机制增加了细胞增殖。在这里，我们研究了Aquaporin-2（AQP2）是否也调节Na ⁺ /。 H ⁺交换异构体1依赖性细胞增殖。我们使用两种表达AQP2的皮质收集管模型：一种组成型（WT或AQP2转染的RCCD ₁细胞系）和一种诱导型（对照或加压素诱导的mpkCCD _c14细胞系）。我们发现水通道蛋白2修饰Na ⁺ / H ⁺交换异构体1（NHE1）对细胞增殖的贡献。在表达Aquaporin-2的细胞中，Na⁺ / H ⁺交换异构体1在生理pH下具有抗增殖作用。在酸性介质中，Na ⁺ / H ⁺交换异构体1的贡献仅在表达AQP2的细胞中从抗增殖转变为增殖。我们还发现，在表达AQP2的细胞中，NHE1依赖的增殖变化与应力纤维水平平行变化：在pH 7.4时，Na ⁺ / H ⁺交换异构体1将有利于应力纤维的分解，而在酸中毒时，NHE1将有利于应力纤维。部件。此外，我们发现Na ⁺ / H ⁺交换子对与Aquaporin-2相关的增殖的影响依赖于瞬时受体潜在亚家族V钙通道的活性。总之，我们的数据表明，在收集导管细胞中，水通道Aquaporin-2调节NHE1依赖性细胞增殖。在表达AQP2的细胞中，在生理pH下，Na ⁺ / H ⁺交换异构体1的功能是抗增殖的；在酸性pH下，Na ⁺ / H ⁺交换异构体1的功能是增殖的。我们建议Na ⁺ / H ⁺交换异构体1通过与应力纤维形成的相互作用来调节增殖。