Diabetes Impairs Renal Osmotic Defense by Blunting the FXR-TonEBP Axis and Predisposes to Severe Dehydration-Induced Acute Kidney Injury

Background: Dehydration often leads to kidney-related complications, yet its impact on diabetic patients remains underexplored. This study aimed to investigate the effects of dehydration on diabetic nephropathy(DN) and the underlying mechanisms of injury. Methods: We integrated clinical data from a cohort of 131 patients with dehydration-induced AKI with studies in a streptozotocin-induced diabetic mouse model subjected to intermittent water deprivation. Renal phenotype was assessed alongside evaluation of the protective FXR-TonEBP signaling axis, a key regulator of osmotic adaptation. Results: Clinical analysis identified diabetes as a strong, independent risk factor for poor renal recovery following dehydration (adjusted OR = 5.42, 95% CI: 2.15–13.67, p=0.001). Animal experiments showed that water deprivation exacerbated renal injury, fibrosis, and apoptosis in diabetic mice. Mechanistically, hyperglycemia specifically blunted the dehydration-induced activation of the renal FXR-TonEBP pathway, attenuating the upregulation of its key downstream targets, AQP2 and gp91. This failure to mount an adaptive osmotic response compromises medullary defense. Conclusion: We propose a “two-hit” model wherein chronic hyperglycemic stress synergizes with an acutely blunted FXR-TonEBP response to dehydration, critically predisposing to severe AKI. This axis represents a promising therapeutic target for renoprotection in diabetes.