Yujiro Maeoka, Tanner Bradford, Xiao-Tong Su, Avika Sharma, Chao-Ling Yang, David H Ellison, James A McCormick, Ryan J Cornelius
{"title":"远端曲细管特异性地破坏 COP9 信号体而非其调控靶标 Cullin 3 会导致曲细管损伤。","authors":"Yujiro Maeoka, Tanner Bradford, Xiao-Tong Su, Avika Sharma, Chao-Ling Yang, David H Ellison, James A McCormick, Ryan J Cornelius","doi":"10.1152/ajprenal.00138.2024","DOIUrl":null,"url":null,"abstract":"<p><p>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 <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-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 <i>Slc12a3</i>-Cre-ERT2 mice to delete <i>Cul3</i> (DCT-<i>Cul3</i><sup>-/-</sup>) or <i>Jab1</i> (DCT-<i>Jab1</i><sup>-/-</sup>) only in 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, SPAK, and pNCC abundance. However, neither model demonstrated changes in plasma K<sup>+</sup>, Cl<sup>-</sup>, or TCO<sub>2</sub>, even though no injury was present. Long-term DCT-<i>Jab1</i><sup>-/-</sup> 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-<i>Cul3</i><sup>-/-</sup> 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><sup>-/-</sup> mice developed tubule injury and atrophy of the DCT, suggesting a direct JAB1 effect or dysregulation of other cullins as mechanisms for injury.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Distal convoluted tubule-specific disruption of the COP9 signalosome but not its regulatory target Cullin 3 causes tubular injury.\",\"authors\":\"Yujiro Maeoka, Tanner Bradford, Xiao-Tong Su, Avika Sharma, Chao-Ling Yang, David H Ellison, James A McCormick, Ryan J Cornelius\",\"doi\":\"10.1152/ajprenal.00138.2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <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-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 <i>Slc12a3</i>-Cre-ERT2 mice to delete <i>Cul3</i> (DCT-<i>Cul3</i><sup>-/-</sup>) or <i>Jab1</i> (DCT-<i>Jab1</i><sup>-/-</sup>) only in 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, SPAK, and pNCC abundance. However, neither model demonstrated changes in plasma K<sup>+</sup>, Cl<sup>-</sup>, or TCO<sub>2</sub>, even though no injury was present. Long-term DCT-<i>Jab1</i><sup>-/-</sup> 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-<i>Cul3</i><sup>-/-</sup> 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><sup>-/-</sup> mice developed tubule injury and atrophy of the DCT, suggesting a direct JAB1 effect or dysregulation of other cullins as mechanisms for injury.</p>\",\"PeriodicalId\":93867,\"journal\":{\"name\":\"American journal of physiology. Renal physiology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-08-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of physiology. Renal physiology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1152/ajprenal.00138.2024\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. 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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 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.