COMMD5 counteracts cisplatin-induced nephrotoxicity by maintaining tubular epithelial integrity and autophagy flux.
Am J Physiol Renal Physiol
; 2024 Sep 19.
Article
em En
| MEDLINE
| ID: mdl-39298552
ABSTRACT
Oxidative stress mediated by reactive oxygen species (ROS) contributes to apoptosis of tubular epithelial cells (TECs) and renal inflammation during acute kidney injury (AKI). Copper Metabolism MURR1 domain-containing 5 (COMMD5/HCaRG) shows strong cytoprotective properties. COMMD5 is highly expressed in proximal tubules (PTs), where it controls cell differentiation. We assessed its role in cisplatin-induced AKI using transgenic mice in which COMMD5 is overexpressed in the PTs. Cisplatin caused the accumulation of damaged mitochondria and cellular waste in PTs, thus increasing the apoptosis of TECs. COMMD5 overexpression effectively protected TECs from cisplatin nephrotoxicity by decreasing intracellular ROS levels, mitochondrial dysfunction, and apoptosis through the preservation of tubular epithelial integrity, thus alleviating morphological and functional kidney damage. Excessive ROS production by hydrogen peroxide led to long-term autophagy activation through an increased burden on the autophagy/lysosome degradation system in TECs, and autophagic elimination of damaged mitochondria and cellular waste was compromised. COMMD5 attenuated oxidative injury by increasing autophagy flux, possibly due to a reduction of intracellular ROS levels through maintained tubular epithelial integrity, which decreased JNK/caspase-3-dependent apoptosis. Meanwhile, COMMD5 inhibition by small interfering RNA reduced the resistance of TECs to cisplatin cytotoxicity, as shown by disrupted tubular epithelial integrity and cell viability. These data indicated that COMMD5 protects TECs from drug-induced oxidative stress and toxicity by maintaining tubular epithelial integrity and autophagy flux and ultimately decreases mitochondrial dysfunction and apoptosis. Increasing COMMD5 content in PTs is proposed as a new protective and therapeutic strategy against AKI.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Am J Physiol Renal Physiol
Assunto da revista:
FISIOLOGIA
/
NEFROLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Japão