NEPHROGENIC DIABETES INSIPIDUS: THE CRUCIAL ROLE OF AQUAPORINS

Abstract

Nephrogenic diabetes insipidus (NDI) is a disorder marked by the kidney's inability to concentrate urine despite normal or elevated levels of vasopressin, often due to impairments in aquaporin-2 (AQP2) expression or function. This study investigated the molecular, physiological, and clinical underpinnings of AQP2 dysfunction in both genetic and acquired forms of NDI. In vitro models demonstrated significantly reduced AQP2 expression and membrane trafficking under lithium exposure, hypokalemia, and hypercalcemia. Animal models, including AQP2 knockout mice and lithium-treated cohorts, exhibited pronounced polyuria, decreased urine osmolality, and elevated vasopressin levels, confirming renal insensitivity to antidiuretic hormone. The results were confirmed through clinical data from NDI patients where congenital cases had little expression of AQP2 and were completely unreceptive to vasopressin analogs while the acquired types displayed par/altered receptiveness. Improved urine osmolality and partially restored AQP2 levels through therapeutic interventions, especially, with thiazide and amiloride diuretics indicate that this is modifiable process in AQP2 regulation. The study also reported the effects of imbalance in electrolytes and lithium on upregulating AQP2 that contributed to clarify their effect in acquired NDI. Overall, findings drive home the crucial role of AQP2 in renal water management and indicate potential symptomatic relief and functional healing from selected NDI subtypes via targeted therapies. These results have serious clinical implications and relevance for remedial strategies which seek to reinstate the function of aquaporins.