ChREBP deficiency alleviates apoptosis by inhibiting TXNIP/oxidative stress in diabetic nephropathy

Aims: In the present study, we investigated the effect of carbohydrate responsive element binding protein (ChREBP) on the TXNIP/oxidative stress and apoptosis in diabetic nephropathy. Methods: ChREBP(-/-) mice (8-week old) were produced using the CRISPR/Cas9 gene editing approach. Diabetes was induced in C57BL/6 mice with streptozotocin. HK-2 cells was transfected with plasmid containing either ChREBP shRNA or TXNIP siRNA. Results: Renal expression of ChREBP and thioredoxin-interacting protein (TXNIP) was increased in patients with type 2 diabetes mellitus (T2DM) and diabetic mice. ChREBP deficiency improved renal function, apoptosis as well as endoplasmic reticulum (ER) stress in diabetic mice. In addition, ChREBP deficiency prevented expression levels of TXNIP and NADPH oxidase 4 (Nox4), 8-hydroxydeoxyguanosine (8-OHdG) and heme oxygenase-1 (HO-1) in diabetic kidneys. The increased urinary 8-OHdG level induced by diabetes was also attenuated in ChREBP deficiency mice. Similarly, HG was shown to induce ChREBP expression and nuclear translocation in HK-2 cells. HG-induced apoptosis was inhibited by transfection of ChREBP shRNA plasmid. Moreover, we found that knockdown of ChREBP suppressed HG-induced TXNIP and Nox4 expression, reactive oxygen species (ROS) generation and ER stress in HK-2 cells. Furthermore, TXNIP knockdown effectively abrogated HG-induced apoptosis in HK-2 cells. Conclusions: These results suggest that ChREBP deficiency prevents diabetes-induced apoptosis via inhibiting oxidative stress and ER stress, highlighting ChREBP as a potential therapy target for diabetic nephropathy.

Automated summary

The study showed that ChREBP deficiency can improve the expression of TXNIP in patients with diabetic nephropathy, leading to improved renal function, apoptosis, and ER stress. Additionally, ChREBP deficiency can prevent the increased expression of TXNIP, Nox4, 8-OHdG, and HO-1 in diabetic kidneys, suggesting ChREBP as a potential therapeutic target for diabetic nephropathy.