Distal convoluted tubule-specific disruption of the COP9 signalosome but not its regulatory target Cullin 3 causes tubular injury

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 <i>Cul3</i> or <i>Jab1</i> (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 <i>Slc12a3</i>-Cre-ERT2 mice to delete <i>Cul3</i> (DCT-<i>Cul3</i>^-/-) or <i>Jab1</i> (DCT-<i>Jab1</i>^-/-) only in the DCT and examined the mice after short- and long-term deletion. Short-term DCT-specific knockout of both <i>Cul3</i> and <i>Jab1</i> mice caused elevated WNK4, pSPAK^S373, and pNCC^T53 abundance. However, neither model demonstrated changes in plasma K⁺, Cl^-, or total CO₂, even though no injury was present. Long-term DCT-<i>Jab1</i>^-/- 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-<i>Cul3</i>^-/- 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-<i>Jab1</i>^-/- mice developed tubule injury and atrophy of the DCT, suggesting a direct JAB1 effect or dysregulation of other cullins as mechanisms for injury.<b>NEW & NOTEWORTHY</b> 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.