NAA10 and BTRC drive CREBRF degradation in endoplasmic reticulum stress and renal tubular injury.

backgroundDiabetic kidney disease (DKD) is a frequent complication associated with diabetes. CREBRF was reported to be closely associated with endoplasmic reticulum stress. However, the upstream regulatory mechanism by which CREBRF modulates endoplasmic reticulum stress in DKD renal tubular injury is unknown.

methodsHK-2 cells were treated with high glucose to construct a cellular model of DKD. C57BL/6J mice were injected intraperitoneally with streptozotocin (STZ) to construct an animal model of DKD. Co-IP was employed to assess the interactions between BTRC or NAA10 and CREBRF, as well as the levels of CREBRF acetylation and ubiquitination. Flow cytometry, EdU, and CCK-8 were used to detect apoptosis and proliferation. HE and PAS were performed to test renal histopathological changes. The expression of the above factors and endoplasmic reticulum stress-related proteins was detected by western blot.

resultsCREBRF was downregulated in DKD, and overexpression of CREBRF inhibited endoplasmic reticulum stress to alleviate high glucose-induced renal tubular injury. Additionally, NAA10 promoted acetylation of CREBRF, which facilitated BTRC-mediated ubiquitination and degradation of CREBRF. Finally, NAA10 inhibited CREBRF to promote endoplasmic reticulum stress in high glucose-induced renal tubules.

conclusionNAA10 promoted acetylation of CREBRF, which facilitated ubiquitination and degradation of CREBRF by BTRC, leading to activation of endoplasmic reticulum stress and exacerbation of renal tubular injury in DKD.