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

Abstract

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.

Prescription Pattern of Antibiotics and Their Appropriateness in Patients With Chronic Kidney Disease-an Observational Study in a Tertiary Care Teaching Hospital in South India

“…The response to a drug can be altered by pathologic conditions (acute and chronic illness and kidney disease) by Decreased receptor number (Emax) and sensitivity (EC50), Decreased receptor binding and altered signal transduction. It was found that vancomycin with a time-dependent antibacterial effect showed increased efficacy and decreased toxicity when administered by prolonged infusion rather than short-term infusion [6]. Similar effect is noted with Meropenem and Piperacillin, where the dosage was based on pharmacodynamics regimens.…”

Combination of Docking-Based and Pharmacophore-Based Virtual Screening Identifies Novel Agonists That Target the Urotensin Receptor

“…The UT receptor and endogenous ligands are widely expressed in various tissues from fish to mammals [2,3]. Clinical studies have shown that U-II/UT expression levels are closely associated with a variety of diseases, such as cardiovascular [4], liver [5], and kidney diseases [6]. It has been suggested that U-II may play a key role in glucose and fat metabolism [7][8][9].…”