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COP9 signalosome deletion promotes renal injury and distal convoluted tubule remodeling.

Authors :
Cornelius, Ryan J.
Nelson, Jonathan W.
Xiao-Tong Su
Chao-Ling Yang
Ellison, David H.
Source :
American Journal of Physiology: Renal Physiology; Jul2022, Vol. 323 Issue 1, pF4-F19, 16p
Publication Year :
2022

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 Naþ-Cl-cotransporter (NCC), the main pathway for Naþ 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
1931857X
Volume :
323
Issue :
1
Database :
Complementary Index
Journal :
American Journal of Physiology: Renal Physiology
Publication Type :
Academic Journal
Accession number :
158194983
Full Text :
https://doi.org/10.1152/ajprenal.00436.2021