Uroguanylin Regulates Net Fluid Secretion via the NHE2 Isoform of the Na⁺/H⁺ Exchanger in an Intestinal Cellular Model

Abstract

Uroguanylin (UGN) has been proposed as a key regulator of salt and water intestinal transport. Uroguanylin activates cell-surface guanylate cyclase C receptor (GC-C) and modulates cellular function via cyclic GMP (cGMP), thus increasing electrolyte and net water secretion. It has been suggested that the action of UGN could involve the Na⁺/H⁺ exchanger, but the actual contribution of this transporter still remains unclear. The objective of our study was to investigate the putative effects of UGN on some members of the Na⁺/H⁺ exchanger family (NHEs), as well as to clarify its consequences on transepithelial fluid flow in T84 cells. In order to do so, transepithelial fluid flow (J_v) was studied by optic techniques and intracellular pH (pH_i) was measured with a fluorescence method. Results showed that NHE2 is found at the apical membrane and has a major role in Na⁺ absorption; NHE1 and NHE4 are localized at the basolateral membrane with a house-keeping role in steady state pH_i. In the assayed conditions, cell exposure to apical UGN increases net secretory J_v, without changing short-circuit currents nor transepithelial resistance, and reduces NHE2 activity. Therefore, at physiological pH, the effect on net J_v was produced mainly by a reduction in normal Na⁺ absorption through NHE2, rather than by the stimulation of electrolyte secretion. Our study shows that the effect of UGN on pH_i is GC-C/cGMP-mediated and enhanced by sildenafil, thus involving PDE5 enzyme. Additionally, cell exposure to apical UGN results in intracellular alkalinization, probably due to indirect effects on basolateral NHE1 and NHE4, which have a major role in pH_i regulation.

Uroguanylin: a new actor in the energy balance movie

“…It was initially proposed that the dietary ingestion of salt induces an increase in the secretion of proUGN by EC . proUGN is converted to UGN in the intestine and the renal tubules , leading to an increase of Na + in the urine (Greenberg et al 1997, Nakazato et al 1998, Lessa et al 2012) and a decrease in intestinal Na + absorption (Joo et al 1998, Toriano et al 2011. As part of this entero-renal axis, UGN signaling acts by regulating Na + homeostasis.…”

“…Salt ingestion is not reflected in circulating proUGN levels and does not affect the gastrointestinal expression of uroguanylin (Fellner et al 2016), but high levels of salt intake induce the synthesis of proUGN in the kidney; proUGN is subsequently delivered to the lumen of the nephron in its active form, UGN. The most recent findings on this topic suggest that the regulation of the UGN system by salt consumption takes place mainly in the kidneys and is not related to the intestinal mechanism controlling UGN production (Toriano et al 2011). The natriuretic effect of UGN has been described in UGN-knockout mice, which have hypertension as a consequence of a delay in sodium excretion (Fellner et al 2016).…”

A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation

“…GC-C receptor activation stimulates cyclic guanosine monophosphate production, which increases cystic fibrosis transmembrane conductance regulator activity (15), leading to chloride and bicarbonate secretion into the intestinal lumen. In addition, activation of GC-C signaling decreases the activity of the sodium-hydrogen exchanger, leading to decreased sodium absorption (16). The resulting ionic gradient allows for fluid secretion that serves to hydrate the stool and facilitate BMs (17).…”

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

“…Guanylin (GN) and uroguanylin (UGN) are upstream regulators of apical CFTR and modulate intestinal Na ϩ , Cl Ϫ , fluid, and HCO 3 Ϫ fluxes in mammals (3,50,61). GN and UGN bind to guanylyl cyclase-C (GC-C), a transmembrane receptor on the apical membrane of intestinal tissues (50,52,53), causing an intracellular transduction cascade that increases the formation of cyclic guanosine monophosphate (cGMP).…”