Xanthohumol attenuates TXNIP-mediated renal tubular injury in vitro and in vivo diabetic models

Thioredoxin-interacting protein (TXNIP), as a pivotal protein in the cellular stress response, plays a significant role in the progression of diabetic nephropathy (DN). Consequently, therapeutic strategies aimed at targeting TXNIP may offer novel interventions for patients with DN. Our study is to explore the therapeutic potential of targeting TXNIP in mitigating renal tubular injury induced by hyperglycemia. Cell viability and apoptosis of renal tubular epithelial cells (RTECs) were evaluated using CCK-8, Annexin V/7-AAD, and TUNEL staining after exposure to normal glucose (NG; 5 mM), high glucose (HG; 30 mM), or treatment with TXNIP inhibitors (Xanthohumol, Xan). Furthermore, histochemical staining was utilized to assess the morphological changes in the kidney. Xan was determined to be a potential inhibitor of TXNIP due to its low binding energy value of - 7.433 kcal/mol. Both genetic inhibition of TXNIP using sh-RNA and pharmacological inhibition with Xan were found to reverse HG-induced RTEC apoptosis and inflammatory response. In diabetic mice, administration of Xan resulted in significant improvements in pathological features such as tubular atrophy, tubular injury score, and collagen deposition in the tubulointerstitium. Additionally, treatment with Xan effectively reduced the up-regulation of TXNIP protein expression caused by hyperglycemia. In conclusion, Xan, as a bioactive natural product, has been shown to attenuate hyperglycemia-induced renal tubular injury in both in vitro and in vivo models, potentially through the inhibition of TXNIP expression. Xan has the potential to serve as a therapeutic compound for the treatment of DN.