uroguanylin and Hypertension

The uroguanylin system is a newly discovered endocrine/paracrine system that may have a role in the regulation of salt balance, appetite and gut health. The precursor pro-uroguanylin is predominantly synthesized in the gut, although there may be other sites of synthesis, including the kidney tubules. Products from pro-uroguanylin may mediate natriuresis following oral consumption of a salt load through both GC-C (guanylate cyclase C)-dependent and -independent mechanisms, and recent evidence suggests a role in appetite regulation. Local paracrine effects in the gut through GC-C stimulation may have tumour-suppressing actions through the regulation of cell proliferation and metabolism. Although most information on this system has been derived from knockout models, recent human studies have indicated possible roles in heart failure and renal failure. An improved understanding of the nature of its natriuretic, appetite and tumour-suppressing actions may facilitate the discovery of new therapies for heart failure, obesity and cancer prophylaxis.

Topics: Amino Acid Sequence; Appetite Regulation; Colonic Neoplasms; Endocrine System; Heart Failure; Humans; Hypertension; Intestinal Mucosa; Irritable Bowel Syndrome; Kidney; Models, Biological; Molecular Sequence Data; Natriuretic Peptides; Paracrine Communication; Receptors, Guanylate Cyclase-Coupled; Signal Transduction; Species Specificity

More than 20% of adults in industrialized countries display arterial pressure outside the normal physiological range. For most individuals, the molecular basis of hypertension remains unknown. In some hypertensive persons, a postprandial natriuretic response, normally elicited by a salty meal, is diminished and contributes to body sodium accumulation and plasma volume expansion. An important physiological mechanism ensuring the increased salt excretion following ingestion of salt is based on a luminocrine and endocrine secretion of novel small intestinal peptides--guanylins. Membrane guanylate cyclase receptors mediate effects of these peptides that provide a novel link between the intestine and kidney by means of circulating molecular guanylin forms. It can be expected that the emergence of the novel guanylin signaling pathways will energize search for molecular defects causing hypertension.

Topics: Animals; Gastrointestinal Hormones; Humans; Hypertension; Intestines; Kidney; Natriuresis; Natriuretic Peptides; Peptides; Postprandial Period

Guanylin (GN), uroguanylin (UGN) and the GC-C receptor have been associated with two endocrine axes: the salt and water homeostasis regulating enterorenal axis and the recently described appetite-regulating UGN/GC-C extraintestinal axis. The present work assessed the mRNA expression levels of GN peptides system (GPS) in a model of diet-induced obesity. Male C57BL/6J mice were submitted to either a high-fat high-simple carbohydrate diet (obese) or a normal diet (control). The renal and intestinal GN, UGN and GC-C receptor mRNA expression were evaluated by reverse transcriptase quantitative polymerase chain reaction in both groups, during normo-saline (NS) and high-saline (HS) diet. The diet-induced obesity was accompanied by glucose intolerance and insulin resistance as well as by a significant increase in blood pressure. During NS diet, obese mice presented reduced mRNA expression of GN in ileum and colon, UGN in duodenum, ileum and colon and GC-C in duodenum, jejunum, ileum and colon. This was accompanied by increased UGN mRNA expression in renal cortex. During HS diet, obese mice presented reduced mRNA expression of GN in jejunum as well as reduced mRNA expression of UGN and GC-C in duodenum, jejunum and colon. The data obtained suggest that, in a mouse model of diet-induced obesity, a down-regulation of intestinal mRNA expression of GN, UGN and its GC-C receptor is accompanied by a compensatory increase of renal UGN mRNA expression. We hypothesize that the decrease in gene expression levels of intestinal GPS may contribute to the development of hypertension and obesity during hypercaloric diet intake.

Topics: Animals; Diet; Gastrointestinal Hormones; Gene Expression Profiling; Hypertension; Intestines; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Natriuretic Peptides; Real-Time Polymerase Chain Reaction

To observe the association between uroguanylin G-247A polymorphism and blood pressure/fluid and electrolytes homeostasis.. Uroguanylin genotype was determined by restrictive fragment length polymorphism (RFLP) and blood pressure as well as fluid and electrolytes homeostasis were measured in 442 volunteers from Jing Ning County, ZheJiang Province. Data were analyzed by ANOVA, Generalized Estimating Equations (GEE), and Quantitative Transmission Disequilibrium Test (QTDT).. Ten uroguanylin gene polymorphisms were detected in 40 subjects by direct sequencing, all were reported in the NCBI SNP database. We selected the G-247A polymorphism for genotyping. Compared with G allele carriers, AA homozygotes had a higher urinary volume (P = 0.08), higher excretions of sodium (P = 0.07) and potassium (P < 0.001), but similar systolic and diastolic blood pressure (P > 0.32) both before and after adjustment for sex, age, body-mass index, current smoking, alcohol intake, and antihypertensive treatment.. The uroguanylin G-247A polymorphism was associated with urinary volume and sodium and potassium excretions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Blood Pressure; Child; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptides; Polymorphism, Restriction Fragment Length; Water-Electrolyte Balance; Young Adult

Uroguanylin (gene name: guanylate cyclase activator 2B, GUCA2B) is a peptide regulator of intestinal salt and water transport. It has been reported that the uroguanylin knockout mouse exhibits elevated blood pressure. Therefore, the GUCA2B gene is thought to be a susceptibility gene for essential hypertension (EH). Despite extensive studies, however, the relationship between the GUCA2B gene and EH has not yet been defined. The aim of this study was to assess the association between the human GUCA2B gene and EH. Using four single nucleotide polymorphisms (SNPs), we conducted a genetic association study in 281 EH patients and 279 age-matched normotensive (NT1) individuals. To derive more reliable data, we performed a duplicate case-control study in which we recruited another normotensive group (NT2). There was no significant difference in the overall distribution of alleles for any of the SNPs between the EH and NT1 groups, or between the EH and NT2 groups. Therefore, these four SNPs cannot be the genetic markers for EH. The occurrences of the C-A haplotype (rs883062-rs1047047) and the C-A-G haplotype (rs883062-rs1047047-rs2297566) were significantly higher in the EH group than in the NT1 group (p<0.0001) or the NT2 group (p<0.0001). These results suggest that the C-A haplotype and the C-A-G haplotype of the GUCA2B gene are the genetic markers for EH, and that GUCA2B or a neighboring gene might be a susceptibility gene for EH.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Natriuretic Peptides; Polymorphism, Single Nucleotide