# SENP3 promotes renal tubular epithelial cell apoptosis after ischemia-reperfusion injury via ASS1 deSUMOylation

## TL;DR

SENP3 promotes kidney cell death after injury by altering ASS1 through deSUMOylation, suggesting a new target for treating kidney damage.

## Contribution

Identifies SENP3-ASS1-p53 pathway as a novel mechanism in renal ischemia-reperfusion injury.

## Key findings

- SENP3 deficiency reduces renal damage after ischemia-reperfusion injury.
- ASS1 is a SUMO2/3 target in IRI, modified at K239 and K310.
- SENP3-mediated deSUMOylation of ASS1 activates apoptosis via p53.

## Abstract

The balance between SUMOylation and deSUMOylation critically regulate cellular apoptosis, with SUMO-modified proteins implicated in ischemia/hypoxia injury. However, the specific contributions of SUMO-conjugated proteins in renal ischemia-reperfusion injury (IRI) remain poorly defined. SUMOylation in IRI was investigated Using proximal tubular-specific Senp3 conditional knockout (CKO) mice. While SENP3-deficiency did not induce tubular injury under basal conditions, its significantly attenuated renal damage following IRI. SUMOylation conferred protection against apoptosis in renal tubular epithelia cells during ischemia/hypoxia. Mass spectrometry revealed arginosuccinate synthase 1 (ASS1) as a key SUMO2/3 target (modified at K239 and K310) in IRI progression. Mechanistically, SENP3-mediated deSUMOylation promoted ASS1 nuclear accumulation in post-IRI tubular epithelial cells, subsequently activating the intrinsic apoptosis pathway via p53-dependent transcriptional upregulation. These findings nominate the SENP3-ASS1-p53 axis as a potential therapeutic target for renal IRI.