家族性高钾血症高血压(FHHt;也称为Gordon综合征)是由WNK4的异常积累引起的,该WNK4激活了肾脏远曲小管(DCT)中的NaCl协同转运蛋白(NCC)。cullin3(CUL3)中的突变通过破坏与deddaseCOP9信号体(CSN)的相互作用而引起FHHt。沿着整个肾单位缺失Cul3或Jab1(催化活性CSN亚基)会导致部分FHHt表型,并激活WNK4-SPAK-NCC途径。然而,进行性肾损伤可能阻止高血压,高钾血症,和与FHHt相关的高氯血症代谢性酸中毒。我们假设DCT特异性缺失将更紧密地模拟疾病。我们利用Slc12a3-Cre-ERT2小鼠仅在DCT中删除Cul3(DCT-Cul3-/-)或Jab1(DCT-Jab1-/-),并在短期和长期删除后检查小鼠。短期,Cul3和Jab1小鼠的DCT特异性敲除导致WNK4,SPAK升高,和pNCC丰度。然而,这两个模型都没有显示出血浆K+的变化,Cl-,或TCO2,即使没有受伤。长期DCT-Jab1-/-小鼠表现出显著较低的NCC和小白蛋白丰度,和更高丰度的肾损伤分子1(KIM-1),近端小管损伤的标志。没有受伤,在长期DCT-Cul3-/-小鼠中观察到NCC或小白蛋白的减少。总之,尽管激活了WNK4-SPAK-NCC通路,但防止DCT外损伤并未导致完整的FHHt表型,可能是由于NCC激活不足。长期而言,只有DCT-Jab1-/-小鼠发生DCT小管损伤和萎缩,提示JAB1的直接作用或其他cullins的失调作为损伤机制。
The disease Familial Hyperkalemic Hypertension (FHHt; also known as Gordon Syndrome) is caused by aberrant accumulation of 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 Cul3 or Jab1 (the catalytically active CSN subunit) along the entire nephron causes a partial FHHt phenotype with activation of the WNK4-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 utilized Slc12a3-Cre-ERT2 mice to delete Cul3 (DCT-Cul3-/-) or Jab1 (DCT-Jab1-/-) only in DCT and examined the mice after short- and long-term deletion. Short-term, DCT-specific knockout of both Cul3 and Jab1 mice caused elevated WNK4, SPAK, and pNCC abundance. However, neither model demonstrated changes in plasma K+, Cl-, or TCO2, even though no injury was present. Long-term DCT-Jab1-/- mice showed significantly lower NCC and parvalbumin abundance, and higher abundance of kidney injury molecule 1 (KIM-1), a marker of proximal tubule injury. No injury, or reduction in NCC or parvalbumin were observed in long-term DCT-Cul3-/- 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-Jab1-/- mice developed tubule injury and atrophy of the DCT, suggesting a direct JAB1 effect or dysregulation of other cullins as mechanisms for injury.