"Aquaporin-omics": Mechanisms of Aquaporin-2 Loss in Polyuric Disorders.

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 (hypokalemia-associated NDI, hypercalcemia-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 signaling 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 signaling processes that result in loss of AQP2. KAY 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 of all such models. 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 signaling. These processes cause loss of AQP2 through translational repression, accelerated degradation of proteins and transcriptional repression. Abstract figure legend Water transport in the renal collecting duct is dependent on a water channel protein called aquaporin-2 (upper left). Aquaporin-2 is regulated by vasopressin through unknown signaling processes that result in changes in gene expression at both the level of proteins and the level of mRNA transcripts (upper right). A variety of insults to the kidney result in loss of aquaporin-2 transcript and protein (bottom). Proteomics and RNA-seq transcriptomics were combined to identify three major cellular process responsible for aquaporin-2 loss (blue ellipses). This article is protected by copyright. All rights reserved.