Identification of xanthurenic acid 8- O -β- d -glucoside and xanthurenic acid 8- O -sulfate as human natriuretic hormones

doi:10.1073/pnas.0705553104

Identification of xanthurenic acid 8-O-β-d-glucoside and xanthurenic acid 8-O-sulfate as human natriuretic hormones

*Naturon Pharmaceutical Corporation, New Canaan, CT 06840; and
^‡Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115

Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved September 17, 2007 (received for review June 13, 2007)

Abstract

Hormonal regulation of salt excretion and water balance by the kidneys is well documented. Before 1961, it was widely believed that the glomerular filtration rate and the steroid hormone aldosterone controlled sodium balance in the body. In 1961, deWardener et al. [de Wardener HE, Mills IH, Clapham WF, Hayter CJ (1961) Clin Sci 21:249–258] showed that when these two variables were controlled, the kidney was still able to increase sodium excretion in response to a salt load. Several lines of evidence argued for a small-molecule signal as a definitive modulator of sodium excretion by the kidney. However, the chemical nature of the suspected natriuretic agent remained unknown. Here we report the identification and natriuretic activity of two closely related small molecules isolated from human urine, xanthurenic acid 8-O-β-d-glucoside and xanthurenic acid 8-O-sulfate. The two compounds were partially purified by activity-guided fractionation and subsequently identified by using NMR spectroscopic analyses of enriched active fractions. Both compounds caused substantial and sustained (1- to 2-h) natriuresis in rats and no or minimal concomitant potassium excretion. We believe these compounds constitute a class of kidney hormones that also could influence sodium transport in nonkidney tissues given that these tryptophan metabolites presumably represent evolutionarily old structures.

Footnotes

^†To whom correspondence should be addressed. E-mail: chriscainphyto{at}yahoo.com
Author contributions: C.D.C., F.C.S., S.W.S., M.M., and N.S.B. designed research; C.D.C., F.C.S., S.W.S., and N.S.B. performed research; F.C.S. and M.S. contributed new reagents/analytic tools; C.D.C., F.C.S., S.W.S., M.M., and N.S.B. analyzed data; and C.D.C., F.C.S., S.W.S., M.S., and N.S.B. wrote the paper.
↵ ^§Present address: Boyce Thompson Institute, Cornell University, Ithaca, NY 14853.
Conflict of interest statement: Five of the six authors hold stock in Naturon, which is incorporated in the State of Delaware. The sixth author (F.C.S.) participated as a paid consultant. All costs for the present studies were paid for by Naturon. No dividends have been issued. A patent application on the two molecules (NH and NH-1) has been submitted (patent application no. US 2006-0217322-A1).
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0705553104/DC1.
Abbreviations:

CRD,

chronic renal disease;

NH,

xanthurenic acid 8-O-β-d-glucoside;

NH-1,

xanthurenic acid 8-O-sulfate;

SCC,

short-circuit current.