State-of-the-art-review Mechanisms of action of SGLT2 inhibitors and clinical implications

American Journal of Hypertension, Journal Year: 2024, Volume and Issue: 37(11), P. 841 - 852

Published: July 15, 2024

Abstract BACKGROUND Inhibitors of the Na+-coupled glucose transporter SGLT2 (SGLT2i) primarily shift reabsorption large amounts from kidney’s early proximal tubule to downstream tubular segments expressing SGLT1, and non-reabsorbed is spilled into urine together with some osmotic diuresis. How can this protect kidneys heart failing as observed in individuals without type 2 diabetes? GOAL Mediation analyses identified clinical phenotypes SGLT2i associated improved kidney outcome, including a reduction plasma volume or increase hematocrit, lowering serum urate levels albuminuria. This review outlines how primary effects on explain these phenotypes. RESULTS The physiology tubule-glomerular communication provides basis for acute GFR glomerular capillary pressure, which contributes albuminuria but also long term preservation GFR, at least part by reducing cortex oxygen demand. Functional co-regulation other sodium metabolite transporters explains why initially excrete more than expected are uricosuric, thereby urate. Inhibition reduces gluco-toxicity shifting transport may simulate “systemic hypoxia”, resulting erythropoiesis, diuresis, enhances hematocrit improves blood delivery. Cardio-renal protection provided fasting-like insulin-sparing metabolic phenotype and, potentially, off-target microbiotic formation uremic toxins.

Language: Английский

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How can inhibition of glucose and sodium transport in the early proximal tubule protect the cardiorenal system?

Nephrology Dialysis Transplantation, Journal Year: 2024, Volume and Issue: 39(10), P. 1565 - 1573

Published: March 1, 2024

What mechanisms can link the inhibition of sodium-glucose cotransporter 2 (SGLT2) in early proximal tubule to kidney and heart protection patients with without type diabetes? Due physical functional coupling SGLT2 other sodium metabolite transporters (including NHE3, URAT1), inhibitors (SGLT2i) reduce reabsorption not only glucose, inducing osmotic diuresis, but metabolites plus a larger amount than expected based on alone, thereby reducing volume retention, hypertension hyperuricemia. Metabolic adaptations SGLT2i include fasting-like response, enhanced lipolysis formation ketone bodies that serve as additional fuel for kidneys heart. Making use physiology tubulo-glomerular communication, functionally lower glomerular capillary pressure filtration rate, stress barrier, tubular exposure albumin nephrotoxic compounds, oxygen demand reabsorbing filtered load. Together reduced gluco-toxicity better distribution transport work along nephron, preserve integrity function and, thereby, rate long-term. By shifting downstream, may simulate systemic hypoxia at sensors deep cortex/outer medulla, which stimulates erythropoiesis together enhances hematocrit improves delivery all organs. The described SGLT2-dependent effects be complemented by off-target itself microbiome cardiovascular-effective uremic toxins.

Language: Английский

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Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 5, 2025

Chronic kidney disease (CKD) and the genetic disorder myotonic dystrophy type 1 (DM1) each are associated with progressive muscle wasting, whole-body insulin resistance, impaired systemic metabolism. However, CKD is undocumented in DM1 molecular pathogenesis driving unknown to involve kidney. Here we use urinary extracellular vesicles (EVs), RNA sequencing, droplet digital PCR, predictive modeling identify downregulation of metabolism transcripts Phosphoenolpyruvate carboxykinase-1, 4-Hydroxyphenylpyruvate dioxygenase, Dihydropyrimidinase, Glutathione S-transferase alpha-1, Aminoacylase-1, Electron transfer flavoprotein B DM1. Expression these genes localizes kidney, especially proximal tubule, correlates strength function. In autopsy tissue, characteristic ribonuclear inclusions evident throughout nephron. We show that organic acids acylglycines elevated DM1, correspond enzyme deficits downregulated genes. Our study identifies a previously unrecognized site highlights potential EVs as biomarkers renal metabolic disturbance individuals.

Language: Английский

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Surface-Enhanced Raman Spectroscopy (SERS)-Based Chemometric Modelling for Chronic Renal Failure Using 50 kDa Ultra-Filtration

Analytical Letters, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17

Published: March 28, 2025

Language: Английский

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Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(10), P. 2078 - 2092

Published: Sept. 10, 2024

Language: Английский

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Tissular glucocorticoid reactivating enzyme 11beta-HSD1 drives pathogenic myofibroblast differentiation in chronic kidney disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Chronic kidney disease (CKD) is a growing public health crisis, affecting over 10% of the global population and significantly increasing mortality morbidity. Irrespective its underlying cause, tubulointerstitial fibrosis (TIF) hallmark CKD progression, with myofibroblasts being primary effectors renal fibrosis. Here, we show that 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) critical driver pathogenic myofibroblast differentiation in CKD. Using genetic deletion pharmacological inhibition 11β-HSD1 mouse models, demonstrate marked reduction TIF severity improved function, linked to suppression regulatory (Reg-MF) subpopulation. Single-cell spatial transcriptomics data reveal essential for activation expansion Reg-MFs, which conserved across species predicts worse outcomes patients allograft recipients. These findings establish direct link between activity fibrogenesis, highlighting role during transition from pericytes Reg-MFs. Our results support as promising therapeutic strategy mitigate offering both mechanistic insights translational potential improving patient outcomes.

Language: Английский

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FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production

FEBS Open Bio, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

FAM136A deficiency has been associated with Ménière's disease. However, the underlying mechanism of action this protein remains unclear. We hypothesized that functions in maintaining mitochondria, even HepG2 cells. To better characterize function, we analyzed cellular response caused by its depletion. depletion induced reactive oxygen species (ROS) and reduced both mitochondrial membrane potential ATP production. cleaved caspase‐9 levels did not increase significantly. next investigated why production but lead to apoptosis. Depletion unfolded (UPR mt ) expression gluconeogenic phosphoenolpyruvate carboxykinases (PCK1 PCK2) ketogenic 3‐hydroxy‐3‐methylglutaryl‐CoA synthases (HMGCS1 HMGCS2) were upregulated. Furthermore, accumulation holocytochrome c synthase (HCCS), a interacting enzyme combines heme apocytochrome produce c. Notably, amount cytochrome change significantly depletion, although total increased This observation suggests greater amounts remain unbound FAM136A‐depleted

Language: Английский

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Adaptation responses to salt stress in the gut of Poecilia reticulata

Animal Cells and Systems, Journal Year: 2025, Volume and Issue: 29(1), P. 84 - 99

Published: Jan. 18, 2025

Osmoregulation is essential for the survival of aquatic organisms, particularly teleost fish facing osmotic challenges in environments characterized by variable salinity. While gills are known ion exchange, intestine's role water and salt absorption gaining attention. Here, we investigated adaptive responses intestine to salinity stress guppies (Poecilia reticulata), observing significant morphological transcriptomic alterations. Guppies showed superior tolerance compared zebrafish (Danio rerio). Increasing reduced villus length intestinal diameter guppies, while exhibited damage structure loss goblet cells. Transcriptomic analysis identified key genes involved osmoregulation, tissue remodeling, immune modulation. Upregulated included solute carrier transporters slc2al slc3al, which facilitate transport, as well a transcription factor AP-1 subunit phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic beta, both participate repair growth responses. In contrast, many related innate system (such Tnfaip6) were downregulated, suggesting shift toward prioritization osmoregulatory functions over Interestingly, differential expression adaptation was linked variations epigenetic modifications activity. Transcription factors crucial adapting stress, such bhlhe40, cebpd, gata6, progressively upregulated but remained downregulated zebrafish. Our findings highlight intricate mechanisms P. reticulata, providing insights into involving organisms.

Language: Английский

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The gut–kidney axis is regulated by astragaloside IV to inhibit cyclosporine A-induced nephrotoxicity

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 27, 2025

Introduction Chronic nephrotoxicity caused by CNIs (CICN) manifests clinically as chronic kidney disease (CKD). Astragaloside IV (AS-IV) plays a certain role in the treatment of CKD. This study aimed to verify ameliorative effects AS-IV on CICN and further explore mechanisms underlying modulation “gut–transcriptome–metabolome coexpression network” within context “gut–kidney axis” improve CICN. Methods Five groups 40 mice were studied: normal group (N, olive oil), model (M, CsA, 30 mg kg -−1 d −1 ), low-dose (CsA + AS-IV, 10 high-dose 20 valsartan Val, ). The gut microbiota, renal transcriptome, urine metabolome separately detected construct gut–transcriptome–metabolome network. target species, genes, metabolites evaluated. Results CsA led increased proteinuria deterioration function, accompanied inflammation oxidative stress, whereas improved damage. inhibited intestinal permeability disrupted microbiota structure, increasing abundance Lactobacillus reuteri , Bifidobacterium animalis Ignatzschineria indica Blautia glucerasea. Six pathways related transcription metabolism, including citrate cycle ascorbate aldarate metabolism proximal tubule bicarbonate reclamation glycolysis/gluconeogenesis, ferroptosis, drug metabolism–cytochrome P450 identified. Seven identified 6 pathways, UDP-D-galacturonic acid, 2-phenylethanol glucuronide, dehydroascorbic isopentenyl pyrophosphate, alpha-D-glucose, 3-carboxy-1-hydroxypropylthiamine diphosphate citalopram aldehyde. genes Ugt1a2, Ugt1a9, Ugt1a5, Pck1, Slc7a11, also predicted NONMMUT144584.1, MSTRG.30357.1 ENSMUST00000174821. was highly correlated with function AS-IV. validated. intestinal-derived urinary toxins tissue apoptosis, lipid accumulation, collagen deposition, mitochondrial Conclusion through six energy driven L. alderate tube are important mechanisms.

Language: Английский

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Huangqi and Danshen improve the chronic nephrotoxicity of Cyclosporin A by regulating lipid metabolism

Phytomedicine, Journal Year: 2025, Volume and Issue: 140, P. 156582 - 156582

Published: Feb. 26, 2025

The clinical application of cyclosporine A (CsA) is limited due to nephrotoxicity. Lipid metabolism disorders play important roles in renal injury, but their role CsA nephrotoxicity not yet clear. Huangqi (Astragalus mongholicus Bunge) and Danshen (Salvia miltiorrhiza (HD) ameliorating the CsA, mechanisms still need be fully clarified. This study innovatively aimed analyse coexpression proteins serum metabolites for identification key pathways targets. provides novel insight into mechanism by which HD ameliorates CsA-induced We utilized intervene both vivo vitro models induced CsA. For experiments, we constructed a network metabolites, was used screen pathways. To validate these findings, knocked down vivo. studies, employed MTT, Transwell, flow cytometry, immunofluorescence assays monitor epithelial-mesenchymal transition (EMT) HK-2 cells. Additionally, electron microscopy Seahorse examine effects on mitochondrial structure function. Furthermore, overexpressed Ppara further confirm improves can improve pathological damage function; regulate blood lipids, inflammation oxidative stress indicators; reduce apoptosis tissues. Joint protein metabolomics analyses revealed that two lipid metabolism-related (the PPAR signalling pathway linoleic acid pathway) were coenriched, involving six differential (Cyp2e1, Cyp4a10, Gk, Lpl, Ppara, Pck1) differentially abundant (alpha-Dimorphecolic 12,13-EpOME). Western blot verify expressed proteins. improved accumulation, as demonstrated transmission (TEM) analysis Oil Red O staining. Knockdown affected expression ACOX1 exacerbated RF. In verification significantly inhibited EMT cells overexpression promoted HD-mediated regulation function, reduced apoptosis, ameliorate through protein-serum coexpression, pathway, metabolism. HD-induced upregulation metabolism, function are mechanisms. Ppara/ACOX1/TGF-β1 axis may an this process. These findings offer potential targets future development therapeutic strategies drugs.

Language: Английский

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