Guanylin, Uroguanylin, and Heat-stable Euterotoxin Activate Guanylate Cyclase C and/or a Pertussis Toxin-sensitive G Protein in Human Proximal Tubule Cells

Sindiće, Aleksandra; Basoglu, Candan; Çerçi, Ayhan; Hirsch, Jochen R.; Potthast, Regine; Kühn, Michaela; Ghanekar, Yashoda; Visweswariah, Sandhya S.; Schlatter, Eberhard

doi:10.1074/jbc.m110627200

Cited by 65 publications

(69 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Potthast et al (54) localized GC-C in the mouse kidney only in glomeruli and proximal tubules. In the human kidney, we detected GC-C again only in the kidney cortex and specifically in proximal tubules ( Figure 6) (60,61). In contrary to these findings in mouse and human, in rat kidney, Carrithers et al (58) found mRNA for GC-C in all nephron segments, suggesting differences in tissue distribution of GC-C in different species.…”

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 45%

“…Guanylin peptides increase the intracellular cGMP concentration in a proximal tubule cell line of opossum kidney (OK cells) via the opossum kidney GC-C (OK-GC), which is the analog to the human GC-C (62). Recently, we demonstrated an increase in the cellular cGMP concentration induced by guanylin peptides also in a human proximal tubule cell line (IHKE1) (61). In this cell line, GN and UGN also activated GC-C.…”

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 96%

“…UGN decreases the expression of the Na ϩ / K ϩ -ATPase, which would lower the concentration gradient for Na ϩ and therefore reduce Na ϩ -coupled electrolyte and substrate reabsorption from the tubular lumen (63). According to our own observations in the human proximal tubule cell line, GN and UGN decrease the electrical driving force for Na ϩ reabsorption by inhibiting K ϩ channels via cGMP and depolarizing cells (61). Finally, the increase in cellular cGMP by GN and UGN should, like in the intestine (37), inhibit luminal Na ϩ /H ϩ exchange and thereby reduce Na ϩ and volume reabsorption.…”

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 99%

“…In the human proximal tubule cell line, UGN activated GC-C at pH 5 more pronounced than at pH 8 ( Figure 4). At alkaline pH, when UGN effects on GC-C in these proximal tubular cells were lower, an additional signaling pathway via pertussis toxin-sensitive G-proteins was revealed (61). Therefore, tubular pH can play an important role in activating GN versus UGN signaling pathways and activating different signaling pathways for UGN (Figure 7).…”

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 99%

See 3 more Smart Citations

Cellular Effects of Guanylin and Uroguanylin

Sinđić

Schlatter

2006

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Ingestion of a salty meal induces secretion of guanylin (GN) and uroguanylin (UGN) into the intestinal lumen, where they inhibit Na ؉ absorption and induce Cl ؊ , HCO 3 ؊ , and water secretion. Simultaneously, these hormones stimulate renal electrolyte excretion by inducing natriuresis, kaliuresis, and diuresis. GN and UGN therefore participate in the prevention of hypernatremia and hypervolemia after salty meals. The signaling pathway of GN and UGN in the intestine is well known. They activate enterocytes via guanylate cyclase C (GC-C), which leads to cGMP-dependent inhibition of Na ؉ /H ؉ exchange and activation of the cystic fibrosis transmembrane regulator. In GC-C-deficient mice, GN and UGN still produce renal natriuresis, kaliuresis, and diuresis, suggesting different signaling pathways in the kidney compared with the intestine. Signaling pathways for GN and UGN in the kidney differ along the various nephron segments. In proximal tubule cells, a cGMP-and GC-C-dependent signaling was demonstrated for both peptides. In addition, UGN activates a pertussis toxinsensitive G-protein-coupled receptor. A similar dual signaling pathway is also known for atrial natriuretic peptide. Recently, a cGMP-independent signaling pathway for GN and UGN was also shown in principal cells of the human and mouse cortical collecting duct. Because GN and UGN activate different signaling pathways in specific organs and even within the kidney, this review focuses on more recent findings on cellular effects and signaling mechanisms of these peptides and their pathophysiologic implications in the intestine and the kidney.

show abstract

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 45%

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 96%

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 99%

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 99%

See 2 more Smart Citations

Cellular Effects of Guanylin and Uroguanylin

Sinđić

Schlatter

2006

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the former was more detected and the total amount of uroguanylin bioactivity was increased as shown in Figure 2. Because uroguanylin has another cGMP-independent pathway unlike ANP (22) and downregulates the message for the Na ϩ /K ϩ ATPase ␥-subunit in mice (23), uroguanylin may be a candidate of natriuretic factor for nephrotic animals. However, ANP was previously suspected to be a causative factor for sodium retention in nephrotic syndrome.…”

Section: Discussionmentioning

confidence: 99%

Role of Uroguanylin, a Peptide with Natriuretic Activity, in Rats with Experimental Nephrotic Syndrome

Kikuchi¹,

Fujimoto²,

Fukae³

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Uroguanylin induces natriuresis and diuresis in vivo as well as in vitro and is found mainly in the intestine and the kidney. However, the roles of uroguanylin in nephrotic syndrome, which is associated with sodium and water retention, have not been determined. Therefore, changes in the urine and plasma concentration of immunoreactive uroguanylin (ir-uroguanylin) and its mRNA expression in the kidney and intestine were examined using rats with puromycin aminonucleoside (PAN)-induced nephrosis. Male Sprague-Dawley rats were separated into control and nephrotic groups, and then the urinary excretion of sodium, protein, and ir-uroguanylin was examined over time. The plasma levels and renal and intestinal mRNA expression of uroguanylin at the periods of sodium retention and remarkable natriuresis also were evaluated. The sequential changes of urinary ir-uroguanylin excretion in the nephrotic group were similar to those of urinary sodium excretion. When the urinary excretion of ir-uroguanylin and sodium peaked, the plasma level of ir-uroguanylin also increased compared with that of the control group. Uroguanylin mRNA expression in the kidney increased during the period of sodium retention and then decreased during the period of remarkable natriuresis. Uroguanylin mRNA expression in the small intestines of control and nephrotic rats were identical. However, in a unilateral PAN-induced proteinuria, uroguanylin expression significantly increased in the PAN-perfused kidney compared with that in the opposite kidney. Considering the natriuretic effect of uroguanylin, these results suggested that uroguanylin plays an important role as a natriuretic factor in nephrotic syndrome via both the circulation and the kidney itself. U roguanylin is a small peptide that activates transmembrane guanylate cyclase (GC) C, influences cellular function via intracellular cyclic guanosine monophosphate (cGMP) (1), and induces the urinary excretion of sodium and water in isolated perfused rat kidneys (2) and in mice in vivo (3). Uroguanylin and guanylin are major hormones in one family of cGMP agonists, whereas atriopeptins (atrial natriuretic peptide [ANP], brain natriuretic peptide, and C-type natriuretic peptide) are a separate and distinct family of peptides that act on different GC (GC-A, -B) to signal via cGMP. We reported that uroguanylin excretion into the urine is increased in humans and rats on a high-salt diet compared with those on a low-salt diet (4,5), indicating that uroguanylin functions as an intestinal natriuretic peptide. Moreover, uroguanylin levels are increased in the circulation of patients with renal disease and congestive heart failure (6,7). Forte et al. (8) suggested that uroguanylin participates in the physiologic maintenance of the sodium balance. However, how uroguanylin functions in the pathophysiologic mechanism of nephrotic syndrome, a condition associated with sodium and water retention, remains obscure. The present study examined serial changes in the urine and plasma concentration of immunoreactive urogua...

show abstract

cDNA Display Selection of Interacting Peptide Ligands of the Guanylate Cyclase C Receptor

Ochiai,

Takahashi,

Inokuchi

et al. 2024

Journal of Peptide Science

View full text Add to dashboard Cite

Guanylate cyclase C (GC‐C), a receptor expressed on the apical membrane of intestinal mucosal cells, is activated by heat‐stable enterotoxin (STa) produced by enterotoxigenic Escherichia coli, as well as the endogenous ligands guanylin and uroguanylin. In this study, novel peptides that interact with GC‐C were generated using the cDNA display method, and their binding affinity and biological activity were evaluated. While the linear peptide library did not yield peptides with sufficient affinity for GC‐C, three cyclic peptides (GCC‐P1, GCC‐P2, and GCC‐P3), each containing two cysteine residues within a 15‐residue sequence, were obtained from a cyclic peptide library containing nine‐residue random sequences. GC‐P2 exhibited significant binding affinity in Biacore assays, although the affinity was lower than those reported for known ligands. Notably, GCC‐P2 and GCC‐P3 demonstrated enhanced cGMP activity when used in combination with linaclotide. However, the agonist activity of these peptides was minimal, indicating that further modifications may be necessary to develop them for clinical applications. This study successfully extracted consensus sequences of peptide motifs that bind to GC‐C from a highly diverse nine‐residue random sequence library, which provides fundamental insights for the discovery and optimization of novel GC‐C ligands.

show abstract

Guanylin, Uroguanylin, and Heat-stable Euterotoxin Activate Guanylate Cyclase C and/or a Pertussis Toxin-sensitive G Protein in Human Proximal Tubule Cells

Cited by 65 publications

References 41 publications

Cellular Effects of Guanylin and Uroguanylin

Cellular Effects of Guanylin and Uroguanylin

Role of Uroguanylin, a Peptide with Natriuretic Activity, in Rats with Experimental Nephrotic Syndrome

cDNA Display Selection of Interacting Peptide Ligands of the Guanylate Cyclase C Receptor

Contact Info

Product

Resources

About