β-Arrestin-2 enhances endoplasmic reticulum stress-induced glomerular endothelial cell injury by activating transcription factor 6 in diabetic nephropathy.

BACKGROUND

Glomerular endothelial cell (GENC) injury is a characteristic of early-stage diabetic nephropathy (DN), and the investigation of potential therapeutic targets for preventing GENC injury is of clinical importance.

AIM

To investigate the role of β-arrestin-2 in GENCs under DN conditions.

METHODS

Eight-week-old C57BL/6J mice were intraperitoneally injected with streptozotocin to induce DN. GENCs were transfected with plasmids containing siRNA-β-arrestin-2, shRNA-activating transcription factor 6 (ATF6), pCDNA-β-arrestin-2, or pCDNA-ATF6. Additionally, adeno-associated virus (AAV) containing shRNA-β-arrestin-2 was administered a tail vein injection in DN mice.

RESULTS

The upregulation of β-arrestin-2 was observed in patients with DN as well as in GENCs from DN mice. Knockdown of β-arrestin-2 reduced apoptosis in high glucose-treated GENCs, which was reversed by the overexpression of ATF6. Moreover, overexpression of β-arrestin-2 Led to the activation of endoplasmic reticulum (ER) stress and the apoptosis of GENCs which could be mitigated by silencing of ATF6. Furthermore, knockdown of β-arrestin-2 by the administration of AAV-shRNA-β-arrestin-2 alleviated renal injury in DN mice.

CONCLUSION

Knockdown of β-arrestin-2 prevents GENC apoptosis by inhibiting ATF6-mediated ER stress and . Consequently, β-arrestin-2 may represent a promising therapeutic target for the clinical management of patients with DN.