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Journal of Advanced Research Feb 2024Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure.
INTRODUCTION
Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure.
OBJECTIVE
We aim to elucidate the role of collecting duct NCOR1 in blood pressure (BP) regulation.
METHODS AND RESULTS
Collecting duct NCOR1 knockout (KO) mice manifested increased BP and aggravated vascular and renal injury in an angiotensin II (Ang II)-induced hypertensive model. KO mice also showed significantly higher BP than littermate control (LC) mice in deoxycorticosterone acetate (DOCA)-salt model. Further study showed that collecting duct NCOR1 deficiency aggravated volume and sodium retention after saline challenge. Among the sodium transporter in the collecting duct, the expression of the three epithelial sodium channel (ENaC) subunits was markedly increased in the renal medulla of KO mice. Consistently, BP in Ang II-infused KO mice decreased significantly to the similar level as those in LC mice after amiloride treatment. ChIP analysis revealed that NCOR1 deficiency increased the enrichment of mineralocorticoid receptor (MR) on the promoters of the three ENaC genes in primary inner medulla collecting duct (IMCD) cells. Co-IP results showed interaction between NCOR1 and MR, and luciferase reporter results demonstrated that NCOR1 inhibited the transcriptional activity of MR. Knockdown of MR eliminated the increased ENaC expression in primary IMCD cells isolated from KO mice. Finally, BP was significantly decreased in Ang II-infused KO mice after treatment of MR antagonist spironolactone and the difference between LC and KO mice was abolished.
CONCLUSIONS
NCOR1 interacts with MR to control ENaC activity in the collecting duct and to regulate sodium reabsorption and ultimately BP. Targeting NCOR1 might be a promising tactic to interrupt the volume and sodium retention of the collecting duct in hypertension.
PubMed: 38341030
DOI: 10.1016/j.jare.2024.02.003 -
Acta Pharmaceutica Sinica. B Feb 2024Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in... (Review)
Review
Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (.., SLC2A4/GLUT4), glucose reabsorption (.., SLC5A2/SGLT2), thermogenesis (.., SLC25A7/UCP-1), and ATP production (.., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (/) and metformin (-/- and , /, ). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.
PubMed: 38322335
DOI: 10.1016/j.apsb.2023.09.004 -
Clinical Chemistry and Laboratory... May 2024Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the... (Comparative Study)
Comparative Study
OBJECTIVES
Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the differential diagnosis of hypophosphatemic syndromes. TmP/GFR is typically calculated from fasting plasma and second morning void urine samples, obtained 2 h after the first void (TmP/GFR 2 h). The purpose of this study was to evaluate if TmP/GFR calculated from 24 h urine collection (TmP/GFR 24 h) can be used as an alternative for TmP/GFR 2 h in patients with urine phosphate wasting.
METHODS
We enrolled adult patients with X-linked hypophosphatemia (XLH) or tumor-induced osteomalacia (TIO). All patients underwent blood and urine sample collections, to calculate TmP/GFR 24 h and TmP/GFR 2 h.
RESULTS
Twenty patients (17 XLH and 3 TIO), aged 24-78 years, were included. All patients had low TmP/GFR 2 h (0.35 mmol/L, IQR 0.24-0.47 mmol/L) and TmP/GFR 24 h (0.31 mmol/L, IQR 0.22-0.43 mmol/L). The concordance correlation coefficient between TmP/GFR 2 h and TmP/GFR 24 h was 0.86 (95 % CI: 0.69-0.93), with a systematic bias of 0.05 mmol/L (95 % limits of agreement: -0.10 to 0.20). Furthermore, in 70 % (i.e., 14 patients out of 20) and 80 % (i.e., 16 patients out of 20) of cases the difference between TmP/GFR 2 h and TmP/GFR 24 h was within ±30 % and ±35 %, respectively.
CONCLUSIONS
Despite TmP/GFR 2 and 24 h show a relatively suboptimal agreement, the difference between the two parameters appears to be small and not clinically significant in the setting of adult patients with FGF23-dependent urine phosphate wasting and secondary hypophosphatemia.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Glomerular Filtration Rate; Hypophosphatemia; Kidney Tubules; Osteomalacia; Paraneoplastic Syndromes; Phosphates; Urine Specimen Collection
PubMed: 38295343
DOI: 10.1515/cclm-2023-1292 -
Cureus Dec 2023Diabetes mellitus, a widespread metabolic illness with increasing global occurrence, continues to have a significant impact on public health. Diabetes is a condition... (Review)
Review
Diabetes mellitus, a widespread metabolic illness with increasing global occurrence, continues to have a significant impact on public health. Diabetes is a condition marked by long-term high blood sugar levels. It is caused by a combination of genetic, environmental, and lifestyle factors, which lead to problems with insulin production and insulin resistance. This dysfunctional state disturbs the delicate balance of glucose regulation, promoting the emergence of problems in both large and small blood vessels that have a substantial impact on illness and death rates. Traditional therapy methods have traditionally given more importance to managing blood sugar levels by using insulin sensitizers, secretagogues, and other medications that lower glucose levels. Advancements in our understanding of the underlying mechanisms of diabetes have led to a significant change in approach, focusing on comprehensive therapies that target not only high blood sugar levels but also the accompanying dangers to the heart and kidneys. This study examines the evolving field of diabetes therapies, explicitly highlighting the significance of GLP-1 receptor agonists and SGLT2 inhibitors. These two types of drugs have become essential components in modern diabetes management. GLP-1 receptor agonists replicate the effects of natural glucagon-like peptide-1, leading to insulin production that is reliant on glucose levels, reducing the release of glucagon, and providing cardiovascular advantages that go beyond controlling blood sugar levels. SGLT2 inhibitors, however, act on the process of renal glucose reabsorption, leading to increased excretion of glucose in the urine and showing significant benefits for cardiovascular and renal protection. This extensive investigation seeks to contribute to the ongoing discourse on diabetes therapies by synthesizing existing research. This review aims to provide clinicians, researchers, and policymakers with a comprehensive understanding of the disease background and the specific pharmacological details of GLP-1 receptor agonists, SGLT2 inhibitors, and other related treatments. The goal is to assist them in developing more effective and personalized strategies to tackle the complex challenges presented by diabetes.
PubMed: 38283440
DOI: 10.7759/cureus.51151 -
Pharmaceutics Jan 2024Γ-hydroxybutyric acid (GHB) is widely abused due to its sedative/hypnotic and euphoric effects. In recent years, GHB use has witnessed a notable rise within the LGBTQ+...
Γ-hydroxybutyric acid (GHB) is widely abused due to its sedative/hypnotic and euphoric effects. In recent years, GHB use has witnessed a notable rise within the LGBTQ+ community. GHB is a substrate of monocarboxylate transporters (MCTs) and exhibits nonlinear toxicokinetics, characterized by saturable metabolism, absorption, and renal reabsorption. This study investigates the impact of exogenous testosterone administration on GHB toxicokinetics and toxicodynamics, exploring the potential of MCT1 inhibition as a strategy to counteract toxicity. Ovariectomized (OVX) females and castrated (CST) male Sprague Dawley rats were treated with testosterone or placebo for 21 days. GHB was administered at two doses (1000 mg/kg or 1500 mg/kg i.v.), and the MCT1 inhibitor AR-C 155858 (1 mg/kg i.v.) was administered 5 min after GHB (1500 mg/kg i.v.) administration. Plasma and urine were collected up to 8 h post-dose, and GHB concentrations were quantified via a validated LC/MS/MS assay. Sleep time (sedative/hypnotic effect) was utilized as the toxicodynamic endpoint. Testosterone treatment significantly affected GHB toxicokinetics and toxicodynamics. Testosterone-treated CST rats exhibited significantly lower renal clearance, higher AUC, and increased sedative effect, while testosterone-treated OVX rats demonstrated higher metabolic clearance. AR-C 155858 treatment led to an increase in GHB renal and total clearance together with an improvement in sedative/hypnotic effect. In conclusion, exogenous testosterone treatment induces significant alterations in GHB toxicokinetics and toxicodynamics, and MCT inhibition can serve as a potential therapeutic strategy for GHB overdose in both cisgender and transgender male populations.
PubMed: 38276513
DOI: 10.3390/pharmaceutics16010143 -
Life (Basel, Switzerland) Jan 2024Previous transplantation studies and the concept of 'nephron underdosing' support the idea that the kidney plays a crucial role in the development of essential... (Review)
Review
Previous transplantation studies and the concept of 'nephron underdosing' support the idea that the kidney plays a crucial role in the development of essential hypertension. This suggests that there are genetic factors in the kidney that can either elevate or decrease blood pressure. The kidney normally maintains arterial pressure within a narrow range by employing the mechanism of pressure-natriuresis. Hypertension is induced when the pressure-natriuresis mechanism fails due to both subtle and overt kidney abnormalities. The inheritance of hypertension is believed to be polygenic, and essential hypertension may result from a combination of genetic variants that code for renal tubular sodium transporters or proteins involved in regulatory pathways. The renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are the major regulators of renal sodium reabsorption. Hyperactivity of either the RAAS or SNS leads to a rightward shift in the pressure-natriuresis curve. In other words, hypertension is induced when the activity of RAAS and SNS is not suppressed despite increased salt intake. Sodium overload, caused by increased intake and/or reduced renal excretion, not only leads to an expansion of plasma volume but also to an increase in systemic vascular resistance. Endothelial dysfunction is caused by an increased intracellular Na concentration, which inhibits endothelial nitric oxide (NO) synthase and reduces NO production. The stiffness of vascular smooth muscle cells is increased by the accumulation of intracellular Na and subsequent elevation of cytoplasmic Ca concentration. In contrast to the hemodynamic effects of osmotically active Na, osmotically inactive Na stimulates immune cells and produces proinflammatory cytokines, which contribute to hypertension. When this occurs in the gut, the microbiota may become imbalanced, leading to intestinal inflammation and systemic hypertension. In conclusion, the primary cause of hypertension is sodium overload resulting from kidney dysregulation.
PubMed: 38255734
DOI: 10.3390/life14010119 -
Kardiologia Polska 2024Numerous studies based on assessment of lithium clearance demonstrated higher sodium reabsorption in renal proximal tubules in individuals with hypertension, overweight,...
BACKGROUND
Numerous studies based on assessment of lithium clearance demonstrated higher sodium reabsorption in renal proximal tubules in individuals with hypertension, overweight, obesity, metabolic syndrome, or diabetes.
AIMS
We aimed to assess the influence of angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin-II-receptor antagonists (ARB) treatment on sodium handling.
METHODS
In a sample of 351Caucasian subjects without diuretic treatment with prevailing sodium consumption, we studied associations between renal sodium reabsorption in proximal (FPRNa) and distal (FDRNa) tubules assessed by endogenous lithium clearance and daily sodium intake measured by 24-hour excretion of sodium (UNaV), in the context of obesity and long-term treatment with ACE-I or ARB.
RESULTS
In the entire study population, we found a strong negative association between FPRNa and ACE-I/ARB treatment (b = -19.5; SE = 4.9; P <0.001). Subjects with FPRNa above the median value showed a significant adverse association between FPRNa and age (b = -0.06; SE = 0.02; P = 0.003), with no association with ACE-I/ARB treatment (P = 0.68). In contrast, in subjects with FPRNa below the median value, we found a strongly significant adverse relationship between FPRNa and ACE-I/ARB treatment (b = -30.4; SE = 8.60; P <0.001), with no association with age (P = 0.32).
CONCLUSIONS
ACE-I/ARB long-term treatment modulates FPRNa in the group with lower reabsorption, but not in that with higher than median value for the entire study population.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Lithium; Sodium; Obesity; Angiotensins
PubMed: 38230464
DOI: 10.33963/v.kp.98723 -
Cureus Dec 2023Bartter syndrome is a genetic condition characterized by autosomal recessive inheritance, resulting in impaired salt reabsorption and clinical manifestations such as...
Bartter syndrome is a genetic condition characterized by autosomal recessive inheritance, resulting in impaired salt reabsorption and clinical manifestations such as low/normal blood pressure and extracellular fluid volume depletion. Multiple abnormalities of the electrolytes, including decreased potassium as well as chloride levels and, in some instances, hypomagnesemia, are its defining features. Metabolic alkalosis, hypokalaemia, hypocalcemia, and hypomagnesemia, together with adequate renal function, are all components of the Bartter-like syndrome. It is associated with certain antibiotics and antineoplastic drugs. We report a case of traumatic brain injury with pneumothorax who was on treatment on colistin and presented with metabolic disturbance.
PubMed: 38229782
DOI: 10.7759/cureus.50672 -
Complications Secondary to the Use Of Sglt2 Inhibitors in Oncological Patients: A Series of 5 Cases.European Journal of Case Reports in... 2024Sodium-glucose cotransporter-2 (iSGLT2) inhibitors, which include dapagliflozin, canagliflozin and empagliflozin, are a class of drugs initially used in the oral...
UNLABELLED
Sodium-glucose cotransporter-2 (iSGLT2) inhibitors, which include dapagliflozin, canagliflozin and empagliflozin, are a class of drugs initially used in the oral treatment of diabetes, heart failure and renal failure. They target the reabsorption of glucose in the kidney. Although they bring benefit to patients with these conditions and in general produce few adverse effects, in some cases, iSGLT2 can cause serious adverse effects such as metabolic acidosis, and fungal or bacterial urinary infections. Oncology patients, who in general have a weak immune system and are usually treated with chemotherapy and/or immunotherapy, are more susceptible to this type of adverse events than other patients. For this reason, it is necessary to adequately select the patients eligible to receive this type of drug and evaluate the potential benefits for them. In this series of five cases, we present two cases of metabolic acidosis, two cases of bacterial urinary sepsis, and one case of fungal urinary sepsis that occurred in patients admitted to the Medical Oncology Department of the University Hospital of Salamanca in 2023.
LEARNING POINTS
Adverse events associated with iSGLT2 can lead to serious complications in immunocompromised patients. There have been cases of prolonged admissions with high morbidity and mortality due to bacterial or fungal infections and metabolic acidosis, all of which are side effects derived from their use.In oncology patients, an adequate evaluation of the risk-benefit balance must be conducted before the introduction of new drugs.Studies should be conducted to assess the risk of serious adverse effects in oncology patients undergoing treatment with chemotherapy or immunotherapy.
PubMed: 38223287
DOI: 10.12890/2023_004216 -
Clinical Nephrology. Case Studies 2024Drug-induced hypomagnesemia is an adverse effect with the potential for serious and fatal outcomes. Although rare, chronic use of proton pump inhibitors (PPIs) can cause...
Drug-induced hypomagnesemia is an adverse effect with the potential for serious and fatal outcomes. Although rare, chronic use of proton pump inhibitors (PPIs) can cause hypomagnesemia due to impaired intestinal absorption, mainly attributed to reduced transcellular transport of magnesium via transient receptor potential melastatin 6 (TRPM6) and 7 (TRPM7) channels. However, a reduction of magnesium paracellular absorption due to the downregulation of intestinal claudins has also been reported. PPI-induced hypomagnesemia can trigger other concomitant electrolyte derangements, including hypokalemia, hypocalcemia, hypophosphatemia, and hyponatremia. Here we report two cases of multiple electrolyte disorders associated with PPI-induced hypomagnesemia, the clinical manifestations of which were cardiac arrhythmia, cognitive changes, and seizure crisis. These cases illustrate the need to monitor serum magnesium levels in patients on long-term PPI use, especially in the elderly and those with malabsorptive bowel syndromes or taking loop diuretics and thiazides.
PubMed: 38222324
DOI: 10.5414/CNCS111284