High glucose levels impair the body's renal protective function during water deprivation by blunting the FXR-TonEBP axis

BackgroundDehydration 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. MethodsWe analyzed clinical outcomes in 81 dehydration-induced acute kidney injury patients (35 with diabetes) and validated findings in streptozotocin-induced diabetic mice subjected to intermittent water deprivation (WD). Renal function, histopathology, and molecular markers (FXR, TonEBP, AQP2, gp91, apoptosis regulators) were assessed. ResultsKidney injury was aggravated after water deprivation in patients with diabetics and it is difficult to recover after water supplementation, with poor prognosis. Animal experiments have shown that compared with mice in a normal state, dehydration challenge aggravated renal damage in diabetic mice with increased serum creatinine, pathological damage, and renal interstitial cell apoptosis. Mechanistically, in a normal state FXR-TonEBP axis was enhanced to protect the kidney after water deprivation challenge, but this compensatory protective response was blunted in the diabetic state. ConclusionHyperglycemia blunts the FXR-TonEBP-osmolyte pathway during dehydration, compromising renal medullary protection. Targeting this axis may mitigate dehydration risks in diabetic nephropathy.