Animal models of a variety of
acquired nephrogenic diabetes insipidus (NDI) disorders have identified a common feature: all such models are associated with the loss of
aquaporin-2 (AQP2) from collecting duct principal cells, explaining the associated
polyuria. To discover mechanisms of AQP2 loss, previous investigators have carried out either transcriptomics (
lithium-induced NDI, unilateral
ureteral obstruction,
endotoxin-induced NDI) or proteomics (hypokalaemia-associated NDI, hypercalcaemia-associated NDI, bilateral
ureteral obstruction), yielding contrasting views. Here, to address whether there may be common mechanisms underlying loss of AQP2 in acquired NDI disorders, we have used bioinformatic data integration techniques to combine information from all transcriptomic and proteomic data sets. The analysis reveals roles for autophagy/apoptosis, oxidative stress and inflammatory signalling as key elements of the mechanism that results in loss of AQP2. These processes can cause AQP2 loss through the combined effects of repression of Aqp2 gene transcription, generalized translational repression, and increased autophagic degradation of
proteins including AQP2. Two possible types of stress-sensor
proteins, namely
death receptors and stress-sensitive
protein kinases of the EIF2AK family, are discussed as potential triggers for signalling processes that result in loss of AQP2. KEY POINTS: Prior studies have shown in a variety of animal models of
acquired nephrogenic diabetes insipidus (NDI) that loss of the
aquaporin-2 (
AQP2) protein is a common feature. Investigations of acquired NDI using transcriptomics (
RNA-seq) and proteomics (
protein mass spectrometry) have led to differing conclusions regarding mechanisms of AQP2 loss. Bioinformatic integration of transcriptomic and proteomic data from these prior studies now reveals that acquired NDI models map to three core processes: oxidative stress, apoptosis/autophagy and inflammatory signalling. These processes cause loss of AQP2 through translational repression, accelerated degradation of
proteins, and transcriptional repression.