Inhibitors of Mammalian Aquaporin Water Channels

Abstract

Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and many functions for AQPs have been reported in health and disease. AQP expression is linked to numerous pathologies including tumor metastasis, fluid dysregulation, and traumatic injury. The targeted modulation of AQPs therefore presents an opportunity to develop novel treatments for diverse conditions. Various techniques such as video microscopy, light scattering and fluorescence quenching have been used to test putative AQP inhibitors in both AQP-expressing mammalian cells and heterologous expression systems. The inherent variability within these methods has caused discrepancy and many molecules that are inhibitory in one experimental system (such as tetraethylammonium, acetazolamide, and anti-epileptic drugs) have no activity in others. Some heavy metal ions (that would not be suitable for therapeutic use) and the compound, TGN-020, have been shown to inhibit some AQPs. Clinical trials for neuromyelitis optica treatments using anti-AQP4 IgG are in progress. However, these antibodies have no effect on water transport. More research to standardize high-throughput assays is required to identify AQP modulators for which there is an urgent and unmet clinical need.

Regulation of AQP4 in the Central Nervous System

“…The majority of aquaporins are modulated by at least one metal ion [2,76,77]. Mercury especially has been shown to have an inhibitory effect on almost all AQPs, with the exception of AQP6 to which it has an activating effect [78].…”

“…Aquaporins (AQPs) are a group of selective transmembrane channels which are expressed in every major organ group in the human body [1,2]. While 13 unique AQPs have been identified in the human body thus far, aquaporin-4 (AQP4) has become an interesting therapeutic target in various neurological disorders, due to its variety of functions and widespread expression in the nervous system [3].…”

“…In cerebral edema and ischemia, AQP4 expression is increased [15,16], and inhibition of AQP4 activity, either by knockout or pretreatment with an inhibitor has been shown to cause a reduction in edema size and formation [7,[17][18][19]. However, in vasogenic edema the loss of AQP4 activity actually aggravates the condition, due to the loss of ability to remove excess water from the brain tissue [2,5,16]. In glioblastomas and astrocytomas, AQP4 is upregulated and redistributed, showing a loss of polarized distribution in the end-feet of high grade tumors [12,[20][21][22].…”

The Effects of Salt and Water Loading on Kidney Function in Healthy Undergraduates

“…These protein water channels are inserted into the apical membranes of tubular epithelial cells where they enhance the ability of tubules to reabsorb water, thus conserving it. Although we did not measure AVP, aquaporins, or related compounds in this experiment, our speculation is reasonable because it is based on irrefutable, supporting evidence [17][18][19][20][21].…”

OEsophageal Ion Transport Mechanisms and Significance Under Pathological Conditions

“…Several inhibitors have been identified that are more or less effective in inhibiting AQPs, such as the small molecule inhibitors, TEA and acetazolamide, which can selectively and reversibly inhibit AQP1 and -4 isoforms (Abir-Awan et al, 2019). The recently discovered molecules, DFP00173 and Z433927330 that have been shown to block glyceroporins by reducing channel glycerol permeability (Abir-Awan et al, 2019). Among the heavy metal ions, Cu ions, NiCl 2 and gold compounds proved to be effective in inhibiting AQP3 (Aikman et al, 2018).…”