COP9 signalosome deletion promotes renal injury and distal convoluted tubule remodeling

Ryan J. Cornelius, Jonathan W. Nelson, Xiao Tong Su, Chao Ling Yang, David H. Ellison

Research output: Contribution to journalArticlepeer-review

Abstract

Cullin-RING ligases are a family of E3 ubiquitin ligases that control cellular processes through regulated degradation. Cullin 3 targets with-no-lysine kinase 4 (WNK4), a kinase that activates the Na -Cl- cotransporter (NCC), the main pathway for Na reabsorption in the distal convoluted tubule (DCT). Mutations in the cullin 3 gene lead to familial hyperkalemic hypertension by increasing WNK4 abundance. The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) regulates the activity of cullin-RING ligases by removing the ubiquitin-like protein neural precursor cell expressed developmentally downregulated protein 8. Genetic deletion of the catalytically active CSN subunit, Jab1, along the nephron in mice (KS-Jab1-/-) led to increased WNK4 abundance; however, NCC abundance was substantially reduced. We hypothesized that the reduction in NCC resulted from a cortical injury that led to hypoplasia of the segment, which counteracted WNK4 activation of NCC. To test this, we studied KS-Jab1-/- mice at weekly intervals over a period of 3 wk. The results showed that NCC abundance was unchanged until 3 wk after Jab1 deletion, at which time other DCT-specific proteins were also reduced. The kidney injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin demonstrated kidney injury immediately after Jab1 deletion; however, the damage was initially limited to the medulla. The injury progressed and expanded into the cortex 3 wk after Jab1 deletion coinciding with loss of the DCT. The data indicate that nephron-specific disruption of the cullin-RING ligase system results in a complex progression of tubule injury that leads to hypoplasia of the DCT.

Original languageEnglish (US)
Pages (from-to)F4-F19
JournalAmerican Journal of Physiology - Renal Physiology
Volume323
Issue number1
DOIs
StatePublished - Jul 2022

Keywords

  • JAB1
  • Na -Cl- cotransporter
  • constitutive photomorphogenesis 9 signalosome
  • distal convoluted tubule

ASJC Scopus subject areas

  • Physiology
  • Urology

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