The tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear.

To investigate the physiologic role of claudin-10a, we generated claudin-10a–deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals. We also used electrophysiologic studies to investigate the functionality of isolated proximal tubules, and studied compensatory regulation by pharmacologic intervention, RNA sequencing analysis, Western blot, immunofluorescence staining, and respirometry.

Mice deficient in claudin-10a were fertile and without overt phenotypes. On knockout, claudin-10a was replaced by claudin-2 in all proximal tubule segments. Electrophysiology showed conversion from paracellular anion preference to cation preference and a loss of paracellular Cl^- over HCO₃^- preference. As a result, there was tubular retention of calcium and magnesium, higher urine pH, and mild hypermagnesemia. A comparison with other urine and serum parameters under control conditions and sequential pharmacologic transport inhibition, and unchanged fractional lithium excretion, suggested compensative measures in proximal and distal tubular segments. Changes in proximal tubular oxygen handling and differential expression of genes regulating fatty acid metabolism indicated proximal tubular adaptation. Western blot and immunofluorescence revealed alterations in distal tubular transport.

Claudin-10a is the major paracellular anion channel in the proximal tubule and its deletion causes calcium and magnesium hyper-reabsorption by claudin-2 redistribution. Transcellular transport in proximal and distal segments and proximal tubular metabolic adaptation compensate for loss of paracellular anion permeability.

紧密连接蛋白 claudin-2 和 claudin-10a 分别形成细胞旁阳离子和阴离子通道，并在近端小管中表达。然而，claudin-10a 在肾脏中的生理作用尚不清楚。

为了研究 claudin-10a 的生理作用，我们培育出 claudin-10a 缺陷小鼠，通过 Southern 印迹、蛋白质印迹和免疫荧光染色确认成功敲除，并分析了敲除和野生型动物的尿液和血清。我们还使用电生理学研究来研究分离的近端小管的功能，并通过药物干预、RNA 测序分析、蛋白质印迹、免疫荧光染色和呼吸测定法研究代偿性调节。

claudin-10a 缺陷小鼠可生育且无明显表型。敲除后，所有近端小管段中的 claudin-10a 都被 claudin-2 取代。^{电生理学显示从细胞旁阴离子偏好转变为阳离子偏好，并且细胞旁 Cl -}超过 HCO ₃ ^-的损失偏爱。结果，出现肾小管钙和镁滞留、尿液 pH 值升高和轻度高镁血症。与对照条件下的其他尿液和血清参数和顺序药物转运抑制以及未改变的锂排泄分数进行比较，建议在近端和远端管段采取补偿措施。近端肾小管氧处理的变化和调节脂肪酸代谢的基因差异表达表明近端肾小管适应。Western blot 和免疫荧光揭示了远端肾小管运输的改变。

Claudin-10a 是近端小管中主要的细胞旁阴离子通道，其缺失会通过 claudin-2 再分布导致钙和镁的过度重吸收。近端和远端节段的跨细胞转运和近端肾小管代谢适应补偿了细胞旁阴离子通透性的损失。