Nfkb1 Removal from Proximal Tubule Cells Improves Renal Tubular Outcomes Following Ischemia Reperfusion Injury.

KEY POINTS

Persistent NF-κB signaling associates within injured proximal tubule cells (PTCs) that fail to repair on kidney injury. Removing activity of Nfkb1, a transcriptional effector of NF-κB signaling, in PTCs enhances PTC repair and decreases injury associated fibrosis. Coexpression of and Relb in injured PTCs suggests additional improvement from comprehensive targeting of NF-κB transcriptional regulators.

BACKGROUND

CKD is a significant global health burden. AKI is a risk factor of progression to CKD. Recent studies have linked failure in proximal tubule repair as a potential contributing factor to CKD in mouse and human studies. Failed repair proximal tubule cells (FR-PTCs), initially presenting at the site of maximal sensitivity to ischemia reperfusion injury and spreading to more cortical regions over time, adopt a senescence-associated secretory phenotype linked to activation of the NF-kB pathway. Several transcriptional regulatory factors mediate NF-kB pathway action. Of these, is prominent within FR-PTCs and chromatin studies predict interactions with pathology-associated gene targets.

METHODS

To examine the role of NF-kB in nephron injury outcomes, we removed activity within the nephron lineage of the mouse kidney and examined the kidney's response to bilateral ischemia reperfusion injury.

RESULTS

Single-cell transcriptional analysis showed a significant reduction of inflammation-associated gene expression, including , , , , and , in -deficient FR-PTCs. A reduced pathological signature correlated with normalized expression of genes associated with healthy proximal tubule function, including , , and a number of solute carriers. Single-nucleus Assay for Transposase-Accessible Chromatin seq analysis linked transcriptomic changes to enhancer regulation, particularly marked opening of chromatin for targets of hepatocyte nuclear factor family members associated with normal regulation of gene expression in proximal tubule cells.

CONCLUSIONS

Examining Assay for Transposase-Accessible Chromatin seq motif predictions and performing direct immunolabeling studies suggested , another transcriptional mediator of NF-κB transcriptional responses with overlapping targeting specificity to , may partially compensate for the loss of . These studies support future efforts to remove ongoing NF-κB signaling within nephrons as a potential therapeutic strategy to target the AKI-to-CKD transition.