The factors between BMI and diabetic nephropathy and protective role of the FGF21-SIRT1 axis in diabetic nephropathy.

Obesity and diabetic nephropathy (DN) represent escalating global health burdens. Glomerular mesangial cell (MC) injury, driven by lipotoxicity from free fatty acids like palmitic acid (PA), is central to DN pathogenesis. Fibroblast growth factor 21 (FGF21) regulates metabolism and mitigates obesity-related complications, yet its specific protective mechanisms against PA-induced MC injury remain unclear. This study employed a dual approach. Part I involved a cross-sectional survey of 1,067 type 2 diabetes mellitus (T2DM) patients to identify demographic and clinical risk factors for chronic kidney disease (CKD) using multivariate regression and latent class analysis. Part II utilized human MCs to investigate PA-induced apoptosis and endoplasmic reticulum stress (ERS), evaluating the therapeutic potential of recombinant human FGF21 (rhFGF21) and the involvement of the SIRT1 signaling pathway. A total of 1067 patients with T2DM were involved in the current study, among them, 345 patients with chronic kidney disease (CKD). The percent of females was 50.3%, and the mean age was 59 ± 11.3 years. Multivariate regression analysis showed that age, systolic blood pressure (SBP), duration of diabetes, hyperlipidemia and smoking status were associated with DN. We also performed a potential category analysis of these factors, and the results were derived into three groups. Further analysis found that there was a positive association between the stage of diabetes and the risk factors at high risk levels. We identified that PA increased the levels of pro-apoptotic markers (cleaved caspase-3 and BCL-2 associated X-protein), decreased the expression levels of the anti-apoptotic marker BCL-2, and upregulated the expression levels of the endoplasmic reticulum stress (ERS)-related proteins, glucose-regulated protein 78, activation transcription factor 4, and CHOP. However, all the effects were attenuated by rhFGF21 treatment. In addition, PA increased FGF21 and sirtuin 1 (SIRT1) expression levels, and rhFGF21 further upregulated SIRT1 expression. However, upon SIRT1 knockdown, rhFGF21 did not exert its protective effect on human MCs. Our findings demonstrate that rhFGF21 protects human MCs from PA-induced apoptosis and ERS via the FGF21-SIRT1 signaling cascade. Integrating these molecular insights with clinical risk stratification suggests that targeting the FGF21-SIRT1 pathway, alongside managing modifiable risk factors such as hypertension and hyperlipidemia, offers a promising integrated strategy for preventing and treating diabetic nephropathy.