Uroguanylin, an Intestinal Natriuretic Peptide, Is Delivered to the Kidney as an Unprocessed Propeptide

Abstract

Orally delivered salt stimulates renal salt excretion more effectively than does iv delivered salt. Although the mechanisms that underlie this "postprandial natriuresis" are poorly understood, the peptide uroguanylin (UGn) is thought to be a key mediator. However, the lack of selective assays for UGn gene products has hindered rigorous testing of this hypothesis. Using peptide-specific assays, we now report surprisingly little UGn in rat intestine or plasma. In contrast, prouroguanylin (proUGn), the presumed-inactive precursor of UGn, is plentiful (at least 40 times more abundant than UGn) in both intestine and plasma. The intestine is the likely source of the circulating proUGn because: 1) the proUGn portal to systemic ratio is approximately two under normal conditions, and 2) systemic proUGn levels decrease rapidly after intestinal resection. Together, these data suggest that proUGn itself is actively involved in enterorenal signaling. This is strongly supported by our observation that iv infusion of proUGn at a physiological concentration produces a long-lasting renal natriuresis, whereas previously reported natriuretic effects of UGn have required supraphysiological concentrations. Thus, our data point to proUGn as an endocrine (i.e. circulating) mediator of postprandial natriuresis, and suggest that the propeptide is secreted intact from the intestine into the circulation and processed to an active form at an extravascular site.

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

“…The hypothalamus is devoid of the endogenous GUCY2C cognate ligands, Guca2a (guanylin) and Guca2b (uroguanylin) (Supplemental Figure 3B), consistent with endocrine, rather than paracrine, regulation of GUCY2C. These hormones are secreted into the circulation by the intestine as inactive propeptides (16,17), which require proteolytic hydrolysis to liberate C-terminal active peptides. Prouroguanylin, but not proguanylin, induced satiation in mice ( Figure 7A), reflecting hypothalamic decoding of these endocrine signals through hormone-specific proteolytic activation ( Figure 7B).…”

“…Reagents used included native ST and the inactive analog ST(5-17)Ala, 9,17 Cys(Acm), 5,10 6-14 disulfide (herein referred to as TJU; Bachem). CCK and PYY were obtained from Phoenix Pharmaceuticals Inc. Prouroguanylin and proguanylin were obtained from BioVendor R&D. Exendin-4 was obtained from California Peptide Research Inc.…”

“…Beyond paracrine endolumenal release, these prohormones also undergo endocrine secretion by the gut into the circulation (16,17). However, in the absence of either cognate receptors mediating extralumenal responses to these peptides (18,19) or defined homeostatic mechanisms regulating their endocrine secretion from the gut (20), the precise physiological significance of the GUCY2C endocrine axis remains ambiguous.…”

Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

“…GUANYLIN (GN) AND UROGUANYLIN (Ugn) are structurally related peptides that stimulate secretory activity in the intestine and inhibit sodium reabsorption by the kidneys (4,5,8,12,13,19,24,30,36,37). Both peptides are produced in the gastrointestinal tract; Ugn primarily by enterochromaffin (EC) cells in the small intestine and Gn by goblet cells in the colon (6,27,28,39,40).…”

Endocrine regulation of airway contractility is overlooked

“…As uroguanylin is found in the blood and urine, the possibility that its release from the intestines can act on distant organs such as the airways cannot be precluded, especially in the context of inflammation where vascular permeability is increased. In fact, even in normal conditions, the effects of guanylin peptides on the functions of other organs, such as the kidneys (Moss et al 2008) and the hypothalamus (Valentino et al 2011), are achieved through endocrine mechanisms.…”