The renin-angiotensin system (RAS) plays a critical role in the regulation of arterial blood pressure and electrolyte homeostasis. The renin precursor, prorenin (PR) and its receptor (PRR) are newly discovered components of the RAS that are highly expressed in the brain, and they are able to promote angiotensin II (ANGII) formation and initiate intracellular signaling pathways. However, the mechanisms underlying these actions are still unknown. We used whole cell patch-clamp electrophysiology in hypothalamic slices to examine the effects of mouse prorenin on the excitability of magnocellular neurosecretory neurons of the supraoptic nucleus (SON) of the rat, key neuronal players in fluid/electrolyte and cardiovascular homeostasis.

PR application (2.5nM) resulted in an increase in action potential firing frequency (186%). This effect was blocked by a PR receptor blocker (250nM) and by dialyzing neurons with the Ca²⁺ chelator BAPTA. Conversely, PR effects persisted in the presence of the AT₁ receptor blocker losartan.  In voltage clamp mode, using slow depolarizing ramps, we found that PR diminished (14%) the magnitude of outward currents, between -20mV to +40mV, resulting in a net PR-sensitive inward current, with a reversal potential of -9.5mV. PR effects in voltage-clamp were also abolished with the PRR blocker and with intracellular BAPTA.

According to these results, we conclude that in magnocellular SON neurons, prorenin, acting via the PR receptor, evokes an excitatory effect that is calcium-dependent, and likely involves inhibition of an outward current. These and ongoing experiments on magnocellular and parvocellular neurons of the supraoptic and paraventricular nuclei, will help us understand the mechanisms underlying PRR-mediated actions, which have been associated with the regulation of fluid homeostasis (water intake, urine osmolality, vasopressin release) and cardiovascular function (mean arterial pressure, heart rate), as well as many pathological conditions, such as hypertension.