The thiazide-sensitive sodium chloride cotransporter (NCC) is more abundant in kidneys of females than of males. Because morphological remodeling of the distal convoluted tubule (DCT) is dependent on NCC activity, it has been generally assumed that there is a corresponding sexual dimorphism in the structure of the DCT, leading to a larger female DCT. Until now, this has never been directly examined. Here, optical clearing techniques were combined with antibody labeling of DCT segment markers, state-of-the-art high-speed volumetric imaging and analysis tools to visualize and quantify DCT morphology in male and female mice and study the DCT remodeling response to furosemide. We found an unexpected sex difference in the structure of the DCT. Compared to the males, females have a shorter DCT, a higher cellular density of NCC, and a greater capacity to elongate in response to loop-diuretics. Our study reveals a sexual dimorphism of the DCT. Females express a greater density of NCC transporters in a shorter structure to protect sodium balance in the face of greater basal distal sodium delivery yet have a larger reserve and structural remodeling capacity to adapt to unique physiological stresses. These observations provide insight into mechanisms that may drive sex differences in the therapeutic responses to diuretics.

中文翻译：

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先进的 3D 成像揭示了远端回旋小管性二态性。

噻嗪类敏感氯化钠协同转运蛋白 (NCC) 在女性肾脏中的含量高于男性。由于远曲小管 (DCT) 的形态重塑依赖于 NCC 活动，因此通常认为 DCT 的结构存在相应的性别二态性，从而导致更大的女性 DCT。直到现在，这从未被直接检查过。在这里，光学清除技术与 DCT 片段标记的抗体标记、最先进的高速体积成像和分析工具相结合，以可视化和量化雄性和雌性小鼠的 DCT 形态，并研究 DCT 对速尿的重塑反应。我们在 DCT 的结构中发现了意想不到的性别差异。与男性相比，女性的 DCT 更短，NCC 的细胞密度更高，以及响应袢利尿剂的更大伸长能力。我们的研究揭示了 DCT 的性别二态性。女性在更短的结构中表达更高密度的 NCC 转运蛋白，以在面对更大的基础远端钠输送时保护钠平衡，但具有更大的储备和结构重塑能力以适应独特的生理压力。这些观察结果提供了对可能导致利尿剂治疗反应性别差异的机制的深入了解。