Defining novel transport mechanisms for volume-regulating corticosteroids in the collecting duct of the kidney

Corticosteroids are critical volume-regulating hormones which target the collecting duct of the kidney where they rapidly alter Na+ and H2O transport, a process which underpins the finetuning of total body Na+ balance and maintains our circulating volume. Under physiological conditions the mineralocorticoid aldosterone acts specifically in the collecting duct due to the activity of the enzyme 11HSD2 which converts the much more abundant glucocorticoid cortisol to an inactive metabolite. However, under certain conditions, glucocorticoids may also stimulate Na+ transport. Much is known about the steroid receptors that these hormones bind, subsequent transcriptional events and their effects upon ion transport. Little, however, is known regarding the movement of these hormones beyond their lipophilic nature, endowing them the ability to diffuse freely across plasma membranes.

The Mansley lab have generated transcriptomic profiles mapping the genetic signals underpinning corticosteroid-induced Na+ transport in a cellular model of the collecting duct. This work identified several families of membrane transporters whose expression are regulated by acute treatment with corticosteroids. Preliminary studies revealed that corticosteroids may in fact be actively transported in a directed manner, with asymmetrical distribution of hormones on either side of the monolayer and negligible intracellular concentrations. Whilst little has been described in the field regarding active corticosteroid transport specifically in the collecting duct, other groups have shown that corticosteroids can be actively transported elsewhere in the body e.g. brain and adipose tissue.

The key research aims of the project are as follows:
To determine the localisation of putative corticosteroid transporters at cellular and tissue level
To investigate which of the putative transporters are capable of corticosteroid transport
To determine the effects of deleting the identified transporter(s) in a cellular model of the distal nephron