Volume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these swelling-activated channels conduct chloride, amino acids, organic osmolytes, and drugs. Despite VRACs’ role in cell volume regulation, and large osmolarity changes in the kidney, neither the localization nor the function of VRACs in the kidney is known.

Mice expressing epitope-tagged LRRC8 subunits were used to determine the renal localization of all VRAC subunits. Mice carrying constitutive deletions of Lrrc8b–e, or with inducible or cell-specific ablation of Lrrc8a, were analyzed to assess renal functions of VRACs. Analysis included histology, urine and serum parameters in different diuresis states, and metabolomics.

The kidney expresses all five VRAC subunits with strikingly distinct localization. Whereas LRRC8C is exclusively found in vascular endothelium, all other subunits are found in the nephron. LRRC8E is specific for intercalated cells, whereas LRRC8A, LRRC8B, and LRRC8D are prominent in basolateral membranes of proximal tubules. Conditional deletion of LRRC8A in proximal but not distal tubules and constitutive deletion of LRRC8D cause proximal tubular injury, increased diuresis, and mild Fanconi-like symptoms.

VRAC/LRRC8 channels are crucial for the function and integrity of proximal tubules, but not for more distal nephron segments despite their larger need for volume regulation. LRRC8A/D channels may be required for the basolateral exit of many organic compounds, including cellular metabolites, in proximal tubules. Proximal tubular injury likely results from combined accumulation of several transported molecules in the absence of VRAC channels.

容量调节阴离子通道 (VRAC) 是 LRRC8A 与 LRRC8B、-C、-D 或 -E 的各种组合的异六聚体。根据亚基的组成，这些肿胀激活的通道传导氯、氨基酸、有机渗透剂和药物。尽管 VRAC 在细胞体积调节和肾脏中的渗透压变化方面发挥着重要作用，但 VRAC 在肾脏中的定位和功能尚不清楚。

使用表达表位标记的 LRRC8 亚基的小鼠来确定所有 VRAC 亚基的肾脏定位。对携带Lrrc8b – e组成型缺失或Lrrc8a可诱导或细胞特异性消融的小鼠进行分析，以评估 VRAC 的肾功能。分析包括不同利尿状态下的组织学、尿液和血清参数以及代谢组学。

肾脏表达所有五个 VRAC 亚基，且具有明显不同的定位。LRRC8C 仅存在于血管内皮中，而所有其他亚基均存在于肾单位中。LRRC8E 对闰细胞具有特异性，而 LRRC8A、LRRC8B 和 LRRC8D 在近端小管的基底外侧膜中突出。近端肾小管而非远端肾小管中 LRRC8A 的条件性缺失以及 LRRC8D 的组成性缺失会导致近端肾小管损伤、利尿增加和轻度范科尼样症状。

VRAC/LRRC8 通道对于近端肾小管的功能和完整性至关重要，但对于更远端的肾单位段则不然，尽管它们对容量调节的需求更大。近曲小管中许多有机化合物（包括细胞代谢物）的基底外侧出口可能需要 LRRC8A/D 通道。近端肾小管损伤可能是由于在缺乏 VRAC 通道的情况下几种转运分子的联合积累造成的。