WCN26-6146 NKG2D Signaling in Podocyte DNA Damage Drives Cardiorenal Axis and CKD Progression: A Therapeutic Strategy and Prognostic Biomarker

Introduction: Chronic kidney disease-mineral and bone disorder (CKD-MBD) represents a systemic complication of chronic kidney disease, contributing significantly to increased morbidity and mortality.Several experimental models of CKD-MBD have been widely used to induce CKD-MBD-like phenotypes.However, in patients with CKD, renal dysfunction is frequently driven by glomerular pathology, and existing models fail to recapitulate the complex pathophysiology of CKD-MBD.Thus, establishing a pathophysiologically relevant animal model is imperative for elucidating the mechanisms underlying CKD-MBD and developing effective therapeutic interventions.In this study, we aimed to establish a mouse model of CKD-MBD that recapitulates human pathophysiology, using Nephrin-hCD25 (NEP25) transgenic (Tg) mice.Methods: At 8 weeks of age, male NEP25 Tg mice were injected with LMB2 at a dose of 0.9 ng/g body weight.Throughout the study, mice had free access to standard mouse chow or modified AIN93G purified diet.All experiments were conducted with n=3-5, and each experiment was repeated at least three times.Results: Under standard diet conditions, LMB2-treated mice developed proteinuria and glomerulosclerosis.While plasma phosphate (Pi) levels remained unchanged compared to non-treated controls, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) levels were significantly elevated.In contrast, under the AIN93G diet, LMB2treated mice exhibited significant increases in plasma Pi, PTH, and FGF23 levels.Furthermore, under the AIN93G diet, micro-computed tomography analysis revealed marked reductions in bone mineral density and deterioration of trabecular architecture in both cortical and cancellous bone compartments in LMB2-treated mice.In addition, in the vascular smooth muscle of LMB2-treated mice under the AIN93G diet, there was a significant increase in the mRNA expression of RUNX2 and SPP1.Conclusion: These findings indicate that NEP25 transgenic mice represent a valuable and reliable model for analyzing the pathophysiology of CKD-MBD.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.