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phase 1GI & Metabolic

Uroguanylin

Also known as: UGN, Prouroguanylin, Guanylate Cyclase-C Agonist, GUCA2B

Uroguanylin is a 16-amino acid endogenous peptide hormone of the gut-kidney axis that activates guanylate cyclase-C (GC-C) receptors in the intestinal epithelium and kidney. Produced by intestinal enterochromaffin cells after oral sodium intake, uroguanylin signals the kidneys to excrete sodium, forming an enteric-renal natriuretic pathway independent of the cardiac natriuretic peptide system. This gut-kidney signaling axis is a frontier area of research linking intestinal peptide hormones to sodium homeostasis, blood pressure regulation, and colorectal cancer prevention.

4 cited references·5 researched benefits

Quick Answer

Uroguanylin is a 16-amino acid gut hormone that activates guanylate cyclase-C receptors in the intestine and kidneys. Released after eating salt, it creates an enteric natriuretic reflex — signaling kidneys to excrete sodium before blood pressure rises. It also regulates intestinal fluid secretion, appetite, and may protect against colorectal cancer. Phase 1 trials are exploring GC-C agonists for metabolic and gastrointestinal disorders.

Key Facts

Mechanism
Uroguanylin is synthesized as prouroguanylin by intestinal epithelial cells and released into the circulation after oral sodium ingestion. In its active form, it binds the extracellular domain of guanylate cyclase-C (GC-C) receptors on intestinal epithelial cells and renal tubular cells. GC-C activation increases intracellular cyclic GMP (cGMP), which activates CFTR chloride channels in the intestine (promoting fluid secretion) and inhibits sodium-hydrogen exchanger NHE3 in renal proximal tubules (promoting natriuresis). In the kidney, prouroguanylin is converted to active uroguanylin by uroguanylin-converting enzyme. Additionally, cGMP activation of protein kinase GII inhibits intestinal cell proliferation, providing tumor-suppressive signaling in colorectal epithelium.
Research Status
phase 1
Half-Life
~15-30 minutes (circulating prouroguanylin)
Molecular Formula
C₆₈H₁₀₉N₂₁O₂₈S₄
Primary Use
GI & Metabolic
Table of Contents

Benefits

  • Enteric natriuresis — signals kidneys to excrete sodium after oral salt intake, independent of cardiac natriuretic peptidesstrong
  • Intestinal fluid regulation — activates CFTR channels to maintain proper intestinal hydrationstrong
  • Colorectal cancer protection — GC-C signaling suppresses intestinal epithelial proliferation and promotes apoptosis of aberrant cellsmoderate
  • Blood pressure regulation — contributes to postprandial sodium excretion preventing salt-sensitive hypertensionmoderate
  • Appetite suppression — GC-C activation in hypothalamic neurons reduces food intake in preclinical modelspreliminary

Dosage Protocols

RouteDosage RangeFrequencyNotes
Research use only0.1-10 mcg/kgVariable in research protocolsNo approved therapeutic formulation for uroguanylin itself. Related GC-C agonists linaclotide (Linzess) and plecanatide (Trulance) are FDA-approved for IBS-C and CIC at fixed oral doses.
Oral (related GC-C agonists — for reference)Linaclotide 72-290 mcg; Plecanatide 3 mgOnce dailyPlecanatide is a synthetic analog of uroguanylin with a single amino acid substitution. It is pH-sensitive, activating preferentially in the mildly acidic upper GI environment.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Diarrhea from excessive intestinal fluid secretion (related GC-C agonists such as linaclotide)common
  • Abdominal discomfort and bloatingcommon
  • Flatulencecommon
  • Dehydration from excessive fluid loss (at high doses)rare
  • Electrolyte imbalances (hyponatremia) with excessive natriuresisserious

Frequently Asked Questions

What is the gut-kidney axis and how does uroguanylin mediate it?
The gut-kidney axis refers to the hormonal communication pathway between the intestine and kidneys that regulates sodium balance after meals. When you eat salt, intestinal cells release prouroguanylin into the bloodstream. In the kidneys, this is converted to active uroguanylin, which activates GC-C receptors on tubular cells to promote sodium excretion. This allows the body to begin excreting dietary sodium before it raises blood pressure — a feedforward mechanism independent of the cardiac natriuretic peptide system (ANP/BNP) that responds to volume overload after the fact.
How does uroguanylin relate to the drugs linaclotide and plecanatide?
Linaclotide (Linzess) and plecanatide (Trulance) are both synthetic GC-C agonists inspired by the uroguanylin/guanylin peptide system. Plecanatide is particularly relevant — it is a synthetic analog of uroguanylin with a single amino acid change that is FDA-approved for chronic idiopathic constipation and IBS with constipation. Linaclotide is structurally related to the bacterial heat-stable enterotoxin (which mimics guanylin). These drugs validate the therapeutic potential of the uroguanylin/GC-C pathway and have annual sales exceeding $1 billion.
Can uroguanylin deficiency contribute to hypertension?
Emerging evidence strongly suggests this. Uroguanylin knockout mice develop salt-sensitive hypertension on a high-sodium diet, despite having intact ANP/BNP and RAAS systems. Obese patients — who have a 3-5 fold increased risk of hypertension — show markedly reduced prouroguanylin levels, suggesting that obesity-related uroguanylin deficiency may contribute to salt-sensitive hypertension. This has led to the hypothesis that the modern epidemic of hypertension is partly driven by uroguanylin silencing from obesity, Western diet, and altered gut microbiome composition.
Does uroguanylin protect against colorectal cancer?
Yes, substantial evidence supports a tumor-suppressive role for uroguanylin-GC-C signaling in the colon. GC-C activation by uroguanylin increases cGMP, which inhibits epithelial cell proliferation, promotes apoptosis, and maintains cell differentiation — all of which oppose cancer development. Critically, uroguanylin expression is lost in >90% of human colorectal cancers, and GC-C knockout mice develop more intestinal tumors. Restoring GC-C signaling with oral plecanatide reduced polyp formation in preclinical models. Clinical trials investigating GC-C agonists for colorectal cancer chemoprevention are being planned.

References

  1. 1
    Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase(1993)PubMed ↗
  2. 2
    Guanylate cyclase-C as a therapeutic target: the uroguanylin–GUCY2C gut-kidney axis in sodium homeostasis(2016)PubMed ↗
  3. 3
    Silencing of guanylin and uroguanylin in colorectal cancer: tumor suppressor pathway implications(2010)PubMed ↗
  4. 4
    Plecanatide (uroguanylin analog) for chronic idiopathic constipation: phase 3 trial results(2017)PubMed ↗

Latest Research

Last updated: 2026-02-19