Epithelial Systems Biology Laboratory, NHLBI
Epithelial Systems Biology Research News
Systems biology identifies signaling mechanisms that defend against body fluid dilution in the syndrome of inappropriate antidiuresis (SIADH).
The level of the antidiuretic hormone, vasopressin, in the bloodstream is normally regulated to precisely control water excretion by the kidney. In many chronically ill patients including those with several forms of cancer, vasopressin and other antidiuretic factors are secreted into the bloodstream in an uncontrolled manner, resulting in water retention and dilution of body fluids. The extent of water retention, however, is limited by the phenomenon of "vasopressin escape" in which the kidney becomes unresponsive to the water-retaining action of vasopressin. In a paper by Lee and colleagues recently published online by the journal Kidney International (1), the molecular signaling processes that account for vasopressin escape have been identified using a technique called "single-tubule RNA-Seq". The authors microdissected collecting duct fragments, containing around 1000 cells, from rat kidneys undergoing vasopressin escape and used next-generation RNA sequencing technique to quantify the messenger RNA molecules produced from each gene. The mRNAs that underwent abundance changes during the onset of vasopressin escape were compared to gene sets associated with known signaling pathways, revealing evidence for activation of transforming growth factor β signaling and epithelial-to-mesenchymal transition (EMT). At the same time, there was a loss of two molecular water channels, aquaporin-2 and aquaporin-3, accounting for the observed increase in water excretion. Addition of transforming growth factor β to collecting duct cells replicated the loss of aquaporin-2. Water channels are the primary route of water transport from urine to blood and their depletion accounts for the loss of the water-retaining effect of vasopressin. Later, there was a shift of the cells from the quiescent state into the cell cycle with arrest, pointing to a partial EMT as a causal event in vasopressin escape.
1. Lee JW, Alsady M, Chou CL, de Groot T, Deen PMT, Knepper MA, Ecelbarger CM. Single-tubule RNA-Seq uncovers signaling mechanisms that defend against hyponatremia in SIADH. Kidney Int. 2017 Aug 23. [Epub ahead of print] PMID: 28843412.