Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States.
LeDucq Transatlantic Network of Excellence, Boston, Massachusetts, United States.
Am J Physiol Renal Physiol. 2024 Oct 1;327(4):F667-F682. doi: 10.1152/ajprenal.00138.2024. Epub 2024 Aug 29.
The disease familial hyperkalemic hypertension (FHHt; also known as Gordon syndrome) is caused by aberrant accumulation of with-no-lysine kinase (WNK4) activating the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the kidney. Mutations in cullin 3 (CUL3) cause FHHt by disrupting interaction with the deneddylase COP9 signalosome (CSN). Deletion of or (the catalytically active CSN subunit) along the entire nephron causes a partial FHHt phenotype with activation of the WNK4-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NCC pathway. However, progressive kidney injury likely prevents hypertension, hyperkalemia, and hyperchloremic metabolic acidosis associated with FHHt. We hypothesized that DCT-specific deletion would more closely model the disease. We used -Cre-ERT2 mice to delete (DCT-) or (DCT-) only in the DCT and examined the mice after short- and long-term deletion. Short-term DCT-specific knockout of both and mice caused elevated WNK4, pSPAK, and pNCC abundance. However, neither model demonstrated changes in plasma K, Cl, or total CO, even though no injury was present. Long-term DCT- mice showed significantly lower NCC and parvalbumin abundance and a higher abundance of kidney injury molecule-1, a marker of proximal tubule injury. No injury or reduction in NCC or parvalbumin was observed in long-term DCT- mice. In summary, the prevention of injury outside the DCT did not lead to a complete FHHt phenotype despite activation of the WNK4-SPAK-NCC pathway, possibly due to insufficient NCC activation. Chronically, only DCT- mice developed tubule injury and atrophy of the DCT, suggesting a direct JAB1 effect or dysregulation of other cullins as mechanisms for injury. CUL3 degrades WNK4, which prevents activation of NCC in the DCT. CSN regulation of CUL3 is impaired in the disease FHHt, causing accumulation of WNK4. Short-term DCT-specific disruption of CUL3 or the CSN in mice resulted in activation of the WNK4-SPAK-NCC pathway but not hyperkalemic metabolic acidosis found in FHHt. Tubule injury was observed only after long-term CSN disruption. The data suggest that disruption of other cullins may be the cause for the injury.
家族性高钾性高血压（FHHt；也称为 Gordon 综合征）是由无赖氨酸激酶（WNK4）在肾脏远曲小管（DCT）中的异常积累引起的，该激酶激活氯化钠共转运蛋白（NCC）。Cullin 3（CUL3）中的突变通过破坏与去泛素化酶 COP9 信号体（CSN）的相互作用而导致 FHHt。整个肾单位中缺失 或 （催化活性的 CSN 亚基）会导致部分 FHHt 表型，WNK4-STE20/SPS1 相关脯氨酸/丙氨酸丰富激酶（SPAK）-NCC 途径被激活。然而，进行性肾损伤可能会阻止与 FHHt 相关的高血压、高钾血症和高氯代谢性酸中毒。我们假设 DCT 特异性缺失将更接近地模拟该疾病。我们使用 -Cre-ERT2 小鼠仅在 DCT 中缺失 （DCT-）或 （DCT-），并在短期和长期缺失后检查小鼠。在短期的 DCT 特异性敲除 和 后，两种模型的 WNK4、pSPAK 和 pNCC 丰度均升高。然而，即使没有损伤，两种模型均未显示血浆 K、Cl 或总 CO 的变化。在长期的 DCT- 小鼠中观察到 NCC 和副甲状腺素的含量显著降低，以及近端小管损伤标志物肾损伤分子-1 的含量增加。在长期的 DCT- 小鼠中未观察到损伤或 NCC 或副甲状腺素的减少。总之，尽管 WNK4-SPAK-NCC 途径被激活，但 DCT 外的损伤预防并未导致完全的 FHHt 表型，这可能是由于 NCC 激活不足。慢性地，只有 DCT- 小鼠才会发生肾小管损伤和 DCT 萎缩，这表明直接的 JAB1 作用或其他 Cullin 的失调可能是损伤的机制。CUL3 降解 WNK4，从而防止 DCT 中 NCC 的激活。在 FHHt 中，CSN 对 CUL3 的调节受损，导致 WNK4 的积累。在小鼠中短期的 DCT 特异性 CUL3 或 CSN 破坏导致 WNK4-SPAK-NCC 途径的激活，但不会导致 FHHt 中发现的高钾代谢性酸中毒。只有在长期的 CSN 破坏后才会观察到肾小管损伤。数据表明，其他 Cullin 的破坏可能是损伤的原因。
