IGFBP5 promotes EndoMT and renal fibrosis through H3K18 lactylation in diabetic nephropathy.

OBJECTIVE

Diabetic nephropathy (DN) is an important complication in diabetic patients that severely impacts their quality of life and life expectancy. Although metabolic and inflammatory responses induced by hyperglycemia are considered the primary pathogenic factors of DN, the specific molecular mechanisms involved remain unclear. Here, we investigated the role of insulin-like growth factor-binding protein 5 (IGFBP5) in DN using in vitro cell experiments and mouse models.

METHODS

We assessed the effects of high-glucose conditions on IGFBP5 expression in glomerular endothelial cells and evaluated its regulatory effects on glycolysis, NLRP3 inflammasome activation, endothelial‒mesenchymal transition (EndoMT), and histone lactylation via the suppression of IGFBP5. Furthermore, we evaluated the effects of IGFBP5 on renal fibrosis and confirmed its regulatory mechanisms in DN model mice.

RESULTS

Knockdown of IGFBP5 inhibited high glucose-induced EndoMT in glomerular endothelial cells, which could also be suppressed by the NLRP3 inflammasome inhibitor MCC950. In addition, silencing of IGFBP5 decreased glycolytic activity and histone lactylation, thereby inhibiting the activation of the NLRP3 inflammasome and EndoMT. Furthermore, in mouse models of DN, IGFBP5 knockdown alleviated renal fibrosis and reduced glycolysis, histone lactylation, NLRP3 inflammasome activation and EndoMT.

CONCLUSIONS

IGFBP5 promotes NLRP3 inflammasome-induced EndoMT and renal fibrosis by regulating glycolysis-mediated histone lactylation, accelerating the progression of DN. These findings provide a new potential therapeutic target for DN.