Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

Abstract

Moss NG, Riguera DA, Fellner RC, Cazzolla C, Goy MF. Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat. Am J Physiol Renal Physiol 299: F1433-F1442, 2010. First published September 22, 2010 doi:10.1152/ajprenal.00281.2010.-The peptide uroguanylin (Ugn) is stored and released as a propeptide (proUgn) by enterochromaffin cells in the intestine, and converted to Ugn and other metabolites in the renal tubules. Both proUgn and Ugn are natriuretic, although the response to proUgn is thought to depend on its conversion to Ugn within nephrons. To assess the efficiency of intrarenal conversion of proUgn to Ugn, we measured urinary Ugn excretion in rats following intravenous infusions of proUgn or Ugn. Infusion of 2 and 10 nmol proUgn/kg body wt increased plasma proUgn concentration from 2.2 Ϯ 0.3 to 5.6 Ϯ 1.3 pmol/ml and to 37 Ϯ 9.6 pmol/ml, respectively. No proUgn was detected in urine before, during, or after proUgn infusions. These two proUgn infusion doses resulted in total Ugn recovery in urine of 162 Ϯ 64 and 206 Ϯ 39 pmol/kg body wt (9 and 2% of the infused amount, respectively). By contrast, the same molar amounts of Ugn resulted in 1,009 Ϯ 477 and 5,352 Ϯ 2,133 pmol/kg body wt of Ugn in urine (recoveries of ϳ50%). Unexpectedly, comparisons of natriuretic dose-response curves for each peptide showed proUgn to be about five times more potent than Ugn, despite the relatively modest amount of Ugn generated from infused proUgn. In addition, both peptides were antikaliuretic at low doses, but in this case Ugn showed greater potency than proUgn. These data do not support Ugn as the primary active principle of proUgn for regulation of renal sodium excretion.

The rat kidney contains high levels of prouroguanylin (the uroguanylin precursor) but does not express GC-C (the enteric uroguanylin receptor)

“…Natriuretic agents that inhibit sodium reabsorption late in the nephron (such as ANP) typically evoke a natriuresis without a significant kaliuresis (70). This is consistent with the previously described saliuretic effects of infused proUgn in the anesthetized rat, where prominent increases in total and fractional sodium excretion were observed with either marginal increases (58) or net decreases (59) in total and fractional excretion of potassium. However, unlike ANP, which acts in the collecting duct exclusively through a cGMP-dependent mechanism (39), our current experiments reveal that the effects of Ugn are strikingly independent of cGMP (Fig.…”

“…It has also been reported that infused proUgn is natriuretic (58,59), presumably because the propeptide is converted to Ugn and other metabolites within the renal tubules (68). Interestingly, a recent study (59) has shown that, mole-formole, proUgn is a more potent natriuretic agent than Ugn, suggesting that intrarenal processing of proUgn may produce an alternate metabolite that is more active than Ugn.…”

“…Interestingly, a recent study (59) has shown that, mole-formole, proUgn is a more potent natriuretic agent than Ugn, suggesting that intrarenal processing of proUgn may produce an alternate metabolite that is more active than Ugn. To test whether proUgn (and/or any of its metabolites) might activate cGMP synthesis, we measured urinary cGMP levels before, during, and after infusion of proUgn at a natriuretic dose of 10 nmol·h Ϫ1 ·kg body wt Ϫ1 .…”

The pendrin anion exchanger gene is transcriptionally regulated by uroguanylin: a novel enterorenal link

“…These studies have shown that proUGN is the endocrine agent released from the intestine into the circulation or produced in the kidney (33) in response to oral salt intake and that it is converted in the kidney to active UGN (42). The same authors have provided evidence for the presence of two UGN isomers with saluretic activity, A and B, which markedly differ in their activity profile (34).…”

“…Recently, Goy and coworkers (32,33,34,42) have thoroughly investigated the biochemical profile and biological activity of the UGN system. These studies have shown that proUGN is the endocrine agent released from the intestine into the circulation or produced in the kidney (33) in response to oral salt intake and that it is converted in the kidney to active UGN (42).…”