Hypertension and kidney disease have been repeatedly associated with genomic variants and alterations of lysine metabolism. Here, we combined stable isotope labeling with untargeted metabolomics to investigate lysine’s metabolic fate in vivo. Dietary 13C6 labeled lysine was tracked to lysine metabolites across various organs. Globally, lysine reacts rapidly with molecules of the central carbon metabolism, but incorporates slowly into proteins and acylcarnitines. Lysine metabolism is accelerated in a rat model of hypertension and kidney damage, chiefly through N-alpha-mediated degradation. Lysine administration diminished development of hypertension and kidney injury. Protective mechanisms include diuresis, further acceleration of lysine conjugate formation, and inhibition of tubular albumin uptake. Lysine also conjugates with malonyl-CoA to form a novel metabolite Nε-malonyl-lysine to deplete malonyl-CoA from fatty acid synthesis. Through conjugate formation and excretion as fructoselysine, saccharopine, and Nε-acetyllysine, lysine lead to depletion of central carbon metabolites from the organism and kidney. Consistently, lysine administration to patients at risk for hypertension and kidney disease inhibited tubular albumin uptake, increased lysine conjugate formation, and reduced tricarboxylic acid (TCA) cycle metabolites, compared to kidney-healthy volunteers. In conclusion, lysine isotope tracing mapped an accelerated metabolism in hypertension, and lysine administration could protect kidneys in hypertensive kidney disease.
Opioid use is associated with predictors of poor cardiorenal outcomes. However, little is known about the direct impact of opioids on podocytes and renal function, especially in the context of hypertension and CKD. We hypothesize that stimulation of opioid receptors (ORs) contributes to dysregulation of intracellular calcium ([Ca2+]i) homeostasis in podocytes, thus aggravating the development of renal damage in hypertensive conditions. Herein, freshly isolated glomeruli from Dahl salt-sensitive (SS) rats and human kidneys, as well as immortalized human podocytes, were used to elucidate the contribution of specific ORs to calcium influx. Stimulation of κ-ORs, but not μ-ORs or δ-ORs, evoked a [Ca2+]i transient in podocytes, potentially through the activation of TRPC6 channels. κ-OR agonist BRL52537 was used to assess the long-term effect in SS rats fed a high-salt diet. Hypertensive rats chronically treated with BRL52537 exhibited [Ca2+]i overload in podocytes, nephrinuria, albuminuria, changes in electrolyte balance, and augmented blood pressure. These data demonstrate that the κ-OR/TRPC6 signaling directly influences podocyte calcium handling, provoking the development of kidney injury in the opioid-treated hypertensive cohort.
Introduction: Dulaglutide (Trulicity â) is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist indicated in adults with type 2 diabetes mellitus. Data about the safety profile of dulaglutide are lacking due to the lack of experience with this recently marketed drug. Material and methods: We report the first case of a beneficial effect of dulaglu-tide. Results: A 48-year-old woman with hypertension, cardiac insufficiency and depression was treated with amlodipine, valsartan, spironolactone, nebivolol, atorvastatine, esomeprazole, escitalopram, oxazepam and tramadol. She had lower limb edema since a lot of months. For diabetes mellitus, dulaglutide (1.5 mg once a week) was started and the lower limb edema began to improve. Three months later, the lower limb edema has disappeared without any new treatment. The dulaglutide had to be interrupted for 2 months and edema recurred. The use of hydrochlorothiazide (25 mg/day) had no effect but the lower limb edema disappeared again after dulaglutide was resumed while all the other drugs were maintained. Discussion/Conclusion: The temporal relationship between dulaglutide treatment and regression of the edema is in favour of the role of dulaglutide and the role of the other drugs, continuously maintained, is ruled out. No regression of edema had been previously reported with dulaglutide. However, animal studies suggest that GLP-1 or its agonists have diuretic and natriuretic effects, which are mediated by an increase in renal plasma flow and glomerular filtration rate, as well as a decrease in the proximal reabsorption of sodium with an increase in fractional sodium excretion [1,2]. Moreover, GLP-1 reduced Na + /H + exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption in the renal proximal tubule, resulting in a decrease of sodium, bicarbonate and water reabsorption. A study in humans concluded that liraglutide, another GLP-1 agonist, decreases the proximal tubular sodium reabsorption, but has no effect on glomerular filtration rate or renal blood flow [3]. Thus, the GLP-1 agonists and especially dulaglutide could probably have a potential interest in disorders of sodium retention. References [1] Crajoinas RO et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am. [3] Skov J et al. Short-term effects of liraglutide on kidney function and vasoac-tive hormones in type 2 diabetes: a randomized clinical trial. Diabetes Obes. Metab. (2016) 18: 581-589. PS1-002 A comparative study of QT prolongation with Serotonin Reuptake Inhibitors (SRIs) A Senard-Ojedo, L Chebane, M Araujo, V Rousseau, F Montastruc, JL Montastruc Laboratoire de Pharmacologie M edicale et Clinique, Centre Midi-Pyr en ees de PharmacoVigilance, de Pharmaco epid emiologie et d'Informations sur le M edicament, Pharmacop^ ole Midi-Pyr en ees, INSERM UMR 1027, CHU et Facult e de M edecine-Toulouse (France) Introduction: QT interval prolongations were described with citalopram or esci-talopram. However, the effects of the other SRIs remai...
Cannabinoids and their endogenous and synthetic analogs impact blood pressure and contribute to the incidence of hypertension. It was previously reported that the endocannabinoid system plays an important role in developing hypertension; however, it was also shown that cannabinoids elicit profound hypotension associated with hemorrhagic, cardiogenic, and endotoxic shock. This study aimed to test acute and chronic effects of an endogenous ligand of cannabinoid receptor anandamide (AEA) on blood pressure and kidney injury in vivo in conscious Dahl salt-sensitive (SS) rats. We demonstrated that acute i.v. bolus administration of a low or a high doses (0.05 or 3 mg/kg) of AEA did not affect blood pressure for 2 h after the injection in Dahl SS rats fed a normal salt diet (0.4% NaCl). Neither low nor high doses of AEA had any beneficial effects on blood pressure or kidney function. Furthermore, hypertensive rats fed a HS diet (8% NaCl) and chronically treated with 3 mg/kg of AEA exhibited a significant increase in blood pressure accompanied by increased renal interstitial fibrosis and glomerular damage at the late stage of hypertension. Western blot analyses revealed increased expression of Smad3 protein levels in the kidney cortex in response to chronic treatment with a high AEA dose. Therefore, TGF-β1/Smad3 signaling pathway may play a crucial role in kidney injury in SS hypertension during chronic treatment with AEA. Collectively, these data indicate that prolonged stimulation of cannabinoid receptors may result in aggravation of hypertension and kidney damage.
Our current knowledge of the properties of renal ion channels responsible for electrolytes and cell energy homeostasis mainly relies on rodent studies. However, it has not been established yet to what extent their characteristics can be generalized to those of humans. The present study was designed to develop a standardized protocol for the isolation of well-preserved glomeruli and renal tubules from rodent and human kidneys and to assess the functional suitability of the obtained materials for physiological studies. Separation of nephron segments from human and rodent kidneys was achieved using a novel vibrodissociation technique. The integrity of isolated renal tubules and glomeruli was probed via electrophysiological analysis and fluorescence microscopy, and the purity of the collected fractions was confirmed using quantitative RT-PCR with gene markers for specific cell types. The developed approach allows rapid isolation of well-preserved renal tubules and glomeruli from human and rodent kidneys amenable for electrophysiological, Ca2+ imaging, and omics studies. Analysis of the basic electrophysiological parameters of major K+ and Na+ channels expressed in human cortical collecting ducts revealed that they exhibited similar biophysical properties as previously reported in rodent studies. Using vibrodissociation for nephron segment isolation has several advantages over existing techniques: it is less labor intensive, requires little to no enzymatic treatment, and produces large quantities of well-preserved experimental material in pure fractions. Applying this method for the separation of nephron segments from human and rodent kidneys may be a powerful tool for the indepth assessment of kidney function in health and disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.