Urotensin II in the development and progression of chronic kidney disease following ⅚ nephrectomy in the rat

Eyre, Heather; Speight, Thomas B.; Glazier, Jocelyn D.; Smith, David M.; Ashton, Nick

doi:10.1113/ep087366

Cited by 14 publications

(10 citation statements)

References 40 publications

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“…Highly upregulated CXCL13 (with 28-fold increase) further argues for the uncontrolled aberrant inflammation in diseased renal tissue (Sato and Yanagita 2017). Gene UTS2, with 19-fold increase in diseased kidney PCTS compared to healthy PCTS, encodes urotensin II that has been shown to promote fibrosis, and its upregulated levels were observed in patients in the later stages of chronic kidney disease (CKD), particularly in individuals requiring dialysis (Eyre et al 2019).…”

Section: Culturing Process Drives a Common Fibrosis-associated State mentioning

confidence: 99%

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

et al. 2019

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Our knowledge of complex pathological mechanisms underlying organ fibrosis is predominantly derived from animal studies. However, relevance of animal models for human disease is limited; therefore, an ex vivo model of human precision-cut tissue slices (PCTS) might become an indispensable tool in fibrosis research and drug development by bridging the animal-human translational gap. This study, presented as two parts, provides comprehensive characterization of the dynamic transcriptional changes in PCTS during culture by RNA sequencing. Part I investigates the differences in culture-induced responses in murine and human PCTS derived from healthy liver, kidney and gut. Part II delineates the molecular processes in cultured human PCTS generated from diseased liver, kidney and ileum. We demonstrated that culture was associated with extensive transcriptional changes and impacted PCTS in a universal way across the organs and two species by triggering an inflammatory response and fibrosis-related extracellular matrix (ECM) remodelling. All PCTS shared mRNA upregulation of IL-11 and ECM-degrading enzymes MMP3 and MMP10. Slice preparation and culturing activated numerous pathways across all PCTS, especially those involved in inflammation (IL-6, IL-8 and HMGB1 signalling) and tissue remodelling (osteoarthritis pathway and integrin signalling). Despite the converging effects of culture, PCTS display species-, organ-and pathologyspecific differences in the regulation of genes and canonical pathways. The underlying pathology in human diseased PCTS endures and influences biological processes like cytokine release. Our study reinforces the use of PCTS as an ex vivo fibrosis model and supports future studies towards its validation as a preclinical tool for drug development.

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Section: Culturing Process Drives a Common Fibrosis-associated State mentioning

confidence: 99%

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

et al. 2019

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“…However, this statement is controversy to our result, which might be due the decrease in renal clearance rates that might have ultimately affected the outcomes of the renal function tests in patients with T2DM in advanced stages, possibly caused by nephropathy and renal failure [46]. To confirm this, our data showed significant increases in the levels of renal function parameters (urea, creatinine, uric acid, and eGFR) along with significant correlations between the two groups [47]. Other diabetic complications include liver injury, fatty liver, and cirrhosis [48].…”

Section: Discussionmentioning

confidence: 43%

Association of Serum Urotensin-II Levels with Insulin Resistance and Endothelin-I in Type-II Diabetes Mellitus Patients

Khidhir

Mahmud

Maulood

2021

eijs

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Urotensin-II (UII), a pluripotent vasoactive cyclic peptide, exhibits the progression of cardiovascular diseases and the glucose metabolic disorder of insulin resistance. Type 2 Diabetes Mellitus (T2DM) is entirely associated with insulin resistance. This study aimed to demonstrate the association of UII with insulin resistance in diabetic and non-diabetic subjects. A total of 73 male and female subjects aged 40-60 years were recruited in this case-control study. They included 35 non- diabetic subjects with a body mass index of (BMI) ≤ 25 and 38 patients with Diabetes Mellitus and BMI ≥ 25. UII levels were assessed beside other vasoactive and clinical parameters. The results revealed that patients with T2DM had elevated UII and Endothelin-I (ET-I) levels, along with positive correlations with the insulin-resistance marker of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), blood pressure (BP), fasting blood glucose (FBG), hemoglobin A1c (HbA1C), and asymmetric dimethylarginine (ADMA). Results from stepwise multiple regressions indicated that UII correlated positively with the increases in the levels of serum cholesterol, ET-I, urea, ADMA, and FBG. This study concludes that the increase in UII level has a positive relation with insulin-resistance and the increase in ET-I level. However, UII could inhibit glucose-induced insulin secretion and, hence, can be utilized as a marker for T2DM and its complications through inflammatory microangiopathy.

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“…Elevation in UII endogenous tone has also been recently demonstrated to contribute to the deterioration of renal function in rat (Eyre et al, 2019). UII is an 11-amino acid vasoactive peptide that possesses a highly conserved cyclic hexapeptide region from fish to mammals (Conlon et al, 1996;Coulouarn et al, 1999).…”

Section: Jpet#265496mentioning

confidence: 99%

Potential Therapeutic Value of Urotensin II Receptor Antagonist in Chronic Kidney Disease and Associated Comorbidities

Ozoux¹,

Briand²,

Pelat³

et al. 2020

J Pharmacol Exp Ther

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Chronic kidney disease (CKD) remains a common disorder leading to growing health and economic burden without curative treatment. In diabetic patients, CKD may result from a combination of metabolic and non-metabolic-related factors with mortality mainly driven by cardiovascular events. The marked overactivity of the urotensinergic system in diabetic patients implicates this vasoactive peptide as a possible contributor to the pathogenesis of renal as well as heart failure. Previous preclinical studies with urotensin II (UII) antagonists in chronic kidney disease were based on simple endpoints that did not reflect the complex etiology of the disease. Given this, our studies revisited the therapeutic value of UII antagonism in CKD and extensively characterize 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino) cyclohexanecarboxylic acid hydrochloride (SAR101099), a potent, selective and orally long-acting UT competitive antagonist inhibiting not only UII but also urotensin related peptide activities. SR101099 treatment more than halved proteinurea and albumin/creatinine ratio in spontaneously-hypertensive stroke-prone-(SHR-SP) rats fed with salt/fat diet and Dahl-salt-sensitive rats, respectively, and halved albuminuria in streptozotocin-induced diabetes rats. Importantly, these effects were accompanied by a decrease in mortality by 50% in SHR-SP and by 35% in the Dahl salt-sensitive rats. SAR101099 was also active on CKD-related cardiovascular pathologies, and partly preserved contractile reserve in models of heart failure induced by myocardial infarction or ischemia/reperfusion in rats and pigs, respectively. SAR101099 exhibited a good safety/tolerability profile at all tested doses in clinical phase-I studies. Together, these data suggest that CKD patient selection considering comorbidities together with new stratification modalities should unveil the urotensin antagonists' therapeutic potential.

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Urotensin II in the development and progression of chronic kidney disease following ⅚ nephrectomy in the rat

Cited by 14 publications

References 40 publications

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

Association of Serum Urotensin-II Levels with Insulin Resistance and Endothelin-I in Type-II Diabetes Mellitus Patients

Potential Therapeutic Value of Urotensin II Receptor Antagonist in Chronic Kidney Disease and Associated Comorbidities

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