The mitochondrial uncoupling protein 2 (UCP2) plays a protective function in the vascular disease of both animal models and humans. UCP2 downregulation upon high-salt feeding favors vascular dysfunction in knock-out mice, and accelerates cerebrovascular and renal damage in the stroke-prone spontaneously hypertensive rat. Overexpression of UCP2 counteracts the negative effects of high-salt feeding in both animal models. We tested in vitro the ability of UCP2 to stimulate autophagy and mitophagy as a mechanism mediating its protective effects upon high-salt exposure in endothelial and renal tubular cells. UCP2 silencing reduced autophagy and mitophagy, whereas the opposite was true upon UCP2 overexpression. High-salt exposure increased level of reactive oxygen species (ROS), UCP2, autophagy and autophagic flux in both endothelial and renal tubular cells. In contrast, high-salt was unable to induce autophagy and autophagic flux in UCP2-silenced cells, concomitantly with excessive ROS accumulation. The addition of an autophagy inducer, Tat-Beclin 1, rescued the viability of UCP2-silenced cells even when exposed to high-salt. In summary, UCP2 mediated the interaction between high-salt-induced oxidative stress and autophagy to preserve viability of both endothelial and renal tubular cells. In the presence of excessive ROS accumulation (achieved upon UCP2 silencing and high-salt exposure of silenced cells) autophagy was turned off. In this condition, an exogenous autophagy inducer rescued the cellular damage induced by excess ROS level. Our data confirm the protective role of UCP2 toward high-salt-induced vascular and renal injury, and they underscore the role of autophagy/mitophagy as a mechanism counteracting the high-salt-induced oxidative stress damage.

An interplay between UCP2 and ROS protects cells from high-salt-induced injury through autophagy stimulation / Forte, Maurizio; Bianchi, Franca; Cotugno, Maria; Marchitti, Simona; Stanzione, Rosita; Maglione, Vittorio; Sciarretta, Sebastiano; Valenti, Valentina; Carnevale, Roberto; Versaci, Francesco; Frati, Giacomo; Volpe, Massimo; Rubattu, Speranza. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 12:10(2021), p. 919. [10.1038/s41419-021-04188-4]

An interplay between UCP2 and ROS protects cells from high-salt-induced injury through autophagy stimulation

Cotugno, Maria;Marchitti, Simona;Stanzione, Rosita;Maglione, Vittorio;Sciarretta, Sebastiano;Carnevale, Roberto;Frati, Giacomo;Volpe, Massimo;Rubattu, Speranza
2021

Abstract

The mitochondrial uncoupling protein 2 (UCP2) plays a protective function in the vascular disease of both animal models and humans. UCP2 downregulation upon high-salt feeding favors vascular dysfunction in knock-out mice, and accelerates cerebrovascular and renal damage in the stroke-prone spontaneously hypertensive rat. Overexpression of UCP2 counteracts the negative effects of high-salt feeding in both animal models. We tested in vitro the ability of UCP2 to stimulate autophagy and mitophagy as a mechanism mediating its protective effects upon high-salt exposure in endothelial and renal tubular cells. UCP2 silencing reduced autophagy and mitophagy, whereas the opposite was true upon UCP2 overexpression. High-salt exposure increased level of reactive oxygen species (ROS), UCP2, autophagy and autophagic flux in both endothelial and renal tubular cells. In contrast, high-salt was unable to induce autophagy and autophagic flux in UCP2-silenced cells, concomitantly with excessive ROS accumulation. The addition of an autophagy inducer, Tat-Beclin 1, rescued the viability of UCP2-silenced cells even when exposed to high-salt. In summary, UCP2 mediated the interaction between high-salt-induced oxidative stress and autophagy to preserve viability of both endothelial and renal tubular cells. In the presence of excessive ROS accumulation (achieved upon UCP2 silencing and high-salt exposure of silenced cells) autophagy was turned off. In this condition, an exogenous autophagy inducer rescued the cellular damage induced by excess ROS level. Our data confirm the protective role of UCP2 toward high-salt-induced vascular and renal injury, and they underscore the role of autophagy/mitophagy as a mechanism counteracting the high-salt-induced oxidative stress damage.
2021
uncoupling protein 2; high-salt; autophagy; endothelial; renal
01 Pubblicazione su rivista::01a Articolo in rivista
An interplay between UCP2 and ROS protects cells from high-salt-induced injury through autophagy stimulation / Forte, Maurizio; Bianchi, Franca; Cotugno, Maria; Marchitti, Simona; Stanzione, Rosita; Maglione, Vittorio; Sciarretta, Sebastiano; Valenti, Valentina; Carnevale, Roberto; Versaci, Francesco; Frati, Giacomo; Volpe, Massimo; Rubattu, Speranza. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 12:10(2021), p. 919. [10.1038/s41419-021-04188-4]
File allegati a questo prodotto
File Dimensione Formato  
Forte_An-interplay_2021.pdf.

accesso aperto

Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: Creative commons
Dimensione 3.63 MB
Formato Unknown
3.63 MB Unknown

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1578779
Citazioni
  • ???jsp.display-item.citation.pmc??? 16
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 20
social impact