Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy

doi:10.1053/j.ajkd.2004.07.021

American Journal of Kidney Diseases

Volume 44, Issue 5, November 2004, Pages 826-831

https://doi.org/10.1053/j.ajkd.2004.07.021 Get rights and content

Background: Urotensin II (UII) is an 11–amino acid vasoactive peptide, recently identified as the ligand for a novel G protein-coupled receptor, GPR-14 (renamed urotensin receptor [UT]). In addition to its potent vasoconstrictive actions, UII also has trophic and profibrotic effects, leading to its implication in the pathogenesis of heart failure. However, elevated plasma UII levels also were reported in association with renal impairment and diabetes. Accordingly, the present study sought to examine the expression and localization of UII and its receptor in kidney tissue from patients with diabetic nephropathy. Methods: We quantified UII and UT gene expression in renal biopsy tissue samples from patients with diabetic nephropathy by using quantitative real-time polymerase chain reaction and determined the intrarenal distribution of their peptides by means of immunohistochemistry. Results: In human diabetic tissue, gene expression of UII and UT were increased 45- and almost 2,000-fold in comparison to control nephrectomy tissue, respectively (P < 0.0001). Immunohistochemical studies showed intense UII peptide staining in diabetic tissue localized predominantly to tubular epithelial cells, and fluorescein-labeled ligand binding studies showed a similar tubular pattern of distribution. Conclusion: In the context of its known biological actions, the dramatic overexpression of UII and its receptor implicate this vasoactive peptide as a possible novel factor in the pathogenesis of diabetic nephropathy.

Section snippets

In vivo studies

Assessment of gene expression and light microscopic studies were performed on surplus renal biopsy tissue obtained for diagnostic purposes from 7 patients with type 2 diabetic nephropathy. Biopsy specimens were divided into 3 portions. One portion was immediately snap frozen in liquid nitrogen and stored at −80°C for subsequent RNA extraction. A second portion was fixed in neutral buffered formalin and embedded in paraffin for later immunohistochemical analysis, and the third portion was frozen

Clinical data

The 7 biopsy specimens obtained for analysis were from patients with type 2 diabetes, and all had evidence of overt nephropathy, as listed in Table 1. Routine clinical biopsy evaluation did not show histopathologic changes apart from those attributable to diabetes. All patients were receiving treatment for hypertension (4 patients, angiotensin-converting enzyme inhibitors; 2 patients, calcium antagonists; 1 patient, diuretic alone). Blood pressures measured at the time of biopsy are listed in

Discussion

The present study shows dramatic overexpression of UII and its receptor in patients with diabetic nephropathy, with a 45-fold increase in ligand gene expression and an almost 2,000-fold increase in receptor expression. In addition, immunohistochemical studies localized both UII peptide and UT receptor binding to tubular epithelial cells in biopsy specimens from patients with diabetic nephropathy, whereas neither was detectable in control tissues.

To date, most studies examining UII and UT have

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The myriad physiologic functions of the kidneys are heavily regulated by the endocrine system. While extrarenal hormones exert well-recognized actions in the urinary system, in recent decades a host of intrinsic, renal hormones, with powerful effects on renal hemodynamics, glomerular filtration, and tubular electrolyte and water handling has been identified. Renal microcirculation, glomerular mesangium, and tubular epithelium produce angiotensin II, the natriuretic peptide urodilatin, vasoconstrictors endothelin-1 and urotensin II, and vasodilators adrenomedullin and intermedin. In addition, new details are emerging regarding the complex regulation of renal calcitriol production. The hematopoietic renal hormone erythropoietin has been found to mitigate ischemic injury to the kidneys, heart, and central nervous system. This chapter presents these products of the endocrine kidney and discusses their renal and systemic physiologic functions, their beneficial versus maladaptive contributions to renal diseases, and their potential exploitation to treat clinical disorders of the kidneys and other organs.
Synthesis and SAR of 5-aryl-furan-2-carboxamide derivatives as potent urotensin-II receptor antagonists
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The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 1, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 1y as a highly potent UT antagonist with an IC₅₀ value of 6 nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile.
Silymarin ameliorates expression of urotensin II (U-II) and its receptor (UTR) and attenuates toxic oxidative stress in the heart of rats with type 2 diabetes
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Citation Excerpt :
U-II receptor (UTR), a member of the G protein-coupled receptors (GPCRs) family also named as GPR14, is highly expressed in the cardiovascular system. In human, the expression of U-II and UTR is upregulated in cardiovascular diseases, including heart failure, hypertension, and coronary artery disease [7] as well as type 2 diabetes [8,9]. There is a positive correlation between the extent of congenital heart failure (CHF) and plasma U-II concentrations [10,11] with 2.1-fold enhancement compared with controls [12].
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD). Urotensin II ((U-II)) and its receptor (UTR) are involved in the progression of CVD through enhancement in the production of reactive oxygen species (ROS). Since silymarin (SMN) is a natural agent with anti-diabetic effects, this study aimed to investigate the antioxidant potency of SMN on the expression of (U-II)/UTR system and oxidative stress status in the heart of type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into six groups (n = 6). Control and diabetic groups treated with or without SMN (60 and 120 mg/kg/day) for 2 months. Fasting blood sugar (FBS), insulin, lipid profile, creatine kinase-MB ((CK-MB)), lactate dehydrogenase (LDH) and markers of oxidative stress were measured by spectrophotometric methods while (U-II) and UTR gene expression was determined by qPCR method. SMN significantly reduced the FBS level, increased the concentration of insulin and improved HOMA-IR. SMN prevented diabetes-induced weight loss, and attenuated the increased levels of total oxidative status (TOS), malondialdehyde (MDA), and nitric oxide (NO). Diabetes-induced reduction of total thiol molecules content (TTM) was normalized to the normal level in SMN treated rats. SMN significantly modulated serum lipid profile, reduced the expression of (U-II) and UTR in the heart, and improved histopathological changes in the heart tissues. Therefore, the current study indicated that SMN ameliorated unpleasant diabetic characteristics via down-regulation of (U-II) and UTR gene expression and modulation of oxidative stress in the heart tissue of type 2 diabetic rats.
Benzo[b]thiophene-2-carboxamide derivatives as potent urotensin-II receptor antagonists
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Members of a series of benzo[b]thiophene-2-carboxamide derivatives, possessing an N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl) group, were synthesized and evaluated as urotensin-II receptor antagonists. The results show that these substances have potent UT binding affinities. Observations made in a systematic SAR investigation of the effects of a variety of substituents (R¹ and R²) at the 5- and 6-positions in the benzo[b]thiophene-2-carboxamide moiety on UT binding affinities led to identification of the 5-cyano analog 7f as a highly potent UT antagonist with an IC₅₀ value of 25 nM. Despite having a good metabolic stability, 7f is a potent inhibitor of CYP isozyme and displays an unsuitable PK profile.

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: Supported in part by grants from the National Health and Medical Research Council of Australia, Juvenile Diabetes Research Foundation International, and St Vincent’s Health, Melbourne. R.E.G. is a recipient of a career development award and D.J.K. is a recipient of a postdoctoral fellowship, both from Juvenile Diabetes Research Foundation International.

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Original investigationsPathogenesis and treatment of kidney disease and hypertensionIncreased expression of urotensin II and urotensin II receptor in human diabetic nephropathy

Section snippets

In vivo studies

Clinical data

Discussion

Lancet

Lancet

Anal Biochem

Kidney Int

Curr Opin Pharmacol

Kidney Int

Regul Pept

Am J Kidney Dis

Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14

Nature

Direct actions of urotensin II on the heartImplications for cardiac fibrosis and hypertrophy

Circ Res

Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1

Endocrinology

Original investigations
Pathogenesis and treatment of kidney disease and hypertension
Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy