mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes DOI Open Access
Dario Troise,

Silvia Mercuri,

Barbara Infante

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8676 - 8676

Published: Aug. 8, 2024

The aging process contributes significantly to the onset of chronic diseases, which are primary causes global mortality, morbidity, and healthcare costs. Numerous studies have shown that removal senescent cells from tissues extends lifespan reduces occurrence age-related diseases. Consequently, there is growing momentum in development drugs targeting these cells. Among them, mTOR SGLT-2 inhibitors garnered attention due their diverse effects: regulate cellular growth, metabolism, immune responses, while glucose reabsorption kidneys, resulting various beneficial metabolic effects. Importantly, may act synergistically by influencing senescence processes pathways. Although direct on combined effects inhibition limited, this review aims highlight potential synergistic benefits senescence.

Language: Английский

Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease DOI
Alla Mitrofanova, Sandra Merscher, Alessia Fornoni

et al.

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(10), P. 629 - 645

Published: July 27, 2023

Language: Английский

Citations

127
Metabolic Communication by SGLT2 Inhibition DOI Creative Commons
A. Billing, Young Chul Kim, Søren Gullaksen

et al.

Circulation, Journal Year: 2023, Volume and Issue: 149(11), P. 860 - 884

Published: Dec. 28, 2023

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or secondary to improvement SGLT2i, we performed an in-depth proteomics, phosphoproteomics, metabolomics analysis integrating signatures from multiple metabolic organs body fluids after 1 week treatment nondiabetic as well diabetic mice with early uncomplicated hyperglycemia. RESULTS: Kidneys reacted most strongly in terms proteomic reconfiguration, including evidence for less proximal tubule glucotoxicity a broad downregulation apical uptake transport machinery (including sodium, glucose, urate, purine bases, amino acids), supported mouse human interactome studies. affected heart liver signaling, more reactive included white adipose tissue, showing lipolysis, and, particularly, gut microbiome, lower relative abundance bacteria taxa capable fermenting phenylalanine tryptophan cardiovascular uremic toxins, resulting plasma levels these compounds p-cresol sulfate). was detectable murine stool samples its addition microbiota fermentation recapitulated some microbiome findings, suggesting direct inhibition aromatic acids tryptophan. In lacking patients decompensated failure diabetes, likewise reduced circulating sulfate, impaired contractility rhythm induced pluripotent stem cell–derived engineered tissue. CONCLUSIONS: formation toxins such sulfate thereby their exposure need renal detoxification, which, combined kidney transporters acid, urate uptake), provides foundation protection.

Language: Английский

Citations

63
Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease DOI
Verónica Miguel, Isaac Shaw, Rafael Kramann

et al.

Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 17, 2024

Language: Английский

Citations

22
The Omics‐Driven Machine Learning Path to Cost‐Effective Precision Medicine in Chronic Kidney Disease DOI Creative Commons
Marta B. Lopes, Roberta Coletti, Flore Duranton

et al.

PROTEOMICS, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

ABSTRACT Chronic kidney disease (CKD) poses a significant and growing global health challenge, making early detection slowing progression essential for improving patient outcomes. Traditional diagnostic methods such as glomerular filtration rate proteinuria are insufficient to capture the complexity of CKD. In contrast, omics technologies have shed light on molecular mechanisms CKD, helping identify biomarkers assessment management. Artificial intelligence (AI) machine learning (ML) could transform CKD care, enabling biomarker discovery diagnosis risk prediction, personalized treatment. By integrating multi‐omics datasets, AI can provide real‐time, patient‐specific insights, improve decision support, optimize cost efficiency by avoidance unnecessary treatments. Multidisciplinary collaborations sophisticated ML advance therapeutic strategies in This review presents comprehensive overview pipeline translating data into treatment, covering recent advances research, role critical need clinical validation AI‐driven discoveries ensure their efficacy, relevance, cost‐effectiveness care.

Language: Английский

Citations

3
Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients DOI Creative Commons
Kumar Sharma, Guanshi Zhang, Jens Hansen

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(20)

Published: Aug. 24, 2023

Diabetic kidney disease (DKD) can lead to end-stage (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes the Chronic Renal Insufficiency Cohort (CRIC) study, Singapore Study of Macro-angiopathy Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), American Indian determined whether urine adenine/creatinine ratio (UAdCR) could be a biomarker ESKD. ESKD mortality were associated highest UAdCR tertile CRIC study SMART2D. was patients macroalbuminuria SMART2D, study. Empagliflozin lowered nonmacroalbuminuric participants. Spatial metabolomics localized adenine pathology, single-cell transcriptomics identified ribonucleoprotein biogenesis as top pathway proximal tubules macroalbuminuria, implicating mTOR. Adenine stimulated matrix tubular cells via mTOR mouse kidneys. A specific inhibitor production found reduce hypertrophy injury diabetic mice. We propose that endogenous may causative factor DKD.

Language: Английский

Citations

30
State-of-the-art-review Mechanisms of action of SGLT2 inhibitors and clinical implications DOI
Volker Vallon

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

Citations

15
Potentials of Natural Antioxidants in Reducing Inflammation and Oxidative Stress in Chronic Kidney Disease DOI Creative Commons

On Ying Angela Lee,

Alex Ngai Nick Wong,

Ching Yan Ho

et al.

Antioxidants, Journal Year: 2024, Volume and Issue: 13(6), P. 751 - 751

Published: June 20, 2024

Chronic kidney disease (CKD) presents a substantial global public health challenge, with high morbidity and mortality. CKD patients often experience dyslipidaemia poor glycaemic control, further exacerbating inflammation oxidative stress in the kidney. If left untreated, these metabolic symptoms can progress to end-stage renal disease, necessitating long-term dialysis or transplantation. Alleviating responses has become standard approach management. Medications such as statins, metformin, GLP-1 agonists, initially developed for treating dysregulation, demonstrate promising therapeutic benefits. The rising popularity of herbal remedies supplements, perceived natural antioxidants, spurred investigations into their potential efficacy. Notably, lactoferrin, Boerhaavia diffusa, Amauroderma rugosum, Ganoderma lucidum are known anti-inflammatory antioxidant properties may support function preservation. However, mechanisms underlying effectiveness Western medications alleviating occurring dysfunction not completely known. This review aims provide comprehensive overview treatment strategies preservation critically discusses existing literature’s limitations whilst offering insight effects interventions. could useful guide future clinical trials facilitate development effective functions.

Language: Английский

Citations

14
How can inhibition of glucose and sodium transport in the early proximal tubule protect the cardiorenal system? DOI
Volker Vallon

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

Citations

13
Glycolytic lactate in diabetic kidney disease DOI Creative Commons

Manjula Darshi,

Luxcia Kugathasan, Soumya Maity

et al.

JCI Insight, Journal Year: 2024, Volume and Issue: 9(11)

Published: June 9, 2024

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) not well defined. Urine lactate was measured patients with type 2 diabetes (T2D) 3 cohorts (HUNT3, SMART2D, CRIC). and plasma were during euglycemic hyperglycemic clamps participants 1 (T1D). Patients the HUNT3 cohort DKD had elevated urine levels compared age- sex-matched controls. In SMART2D CRIC cohorts, third tertile lactate/creatinine associated more rapid estimated glomerular filtration rate decline, relative to first tertile. T1D demonstrated strong association between glucose both urine. Glucose-stimulated likely derives part from proximal tubular cells, since production attenuated sodium-glucose cotransporter-2 (SGLT2) inhibition sections SGLT2-deficient mice. Several glycolytic genes human tubules. above 2.5 mM potently inhibited oxidative phosphorylation tubule (HK2) cells. We conclude that increased under conditions can contribute dysfunction become feed-forward component pathogenesis.

Language: Английский

Citations

13
Narrative Review of Immunomodulatory and Anti-inflammatory Effects of Sodium-Glucose Cotransporter 2 Inhibitors: Unveiling Novel Therapeutic Frontiers DOI Creative Commons
Sul A Lee, Leonardo V. Riella

Kidney International Reports, Journal Year: 2024, Volume and Issue: 9(6), P. 1601 - 1613

Published: March 1, 2024

Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) have evolved from their initial role as anti-diabetic drugs to garner recognition for remarkable cardio-protective and reno-protective attributes. They become a crucial component of therapeutic guidelines congestive heart failure proteinuric chronic kidney disease. These benefits extend beyond glycemic control, improvements in cardiovascular renal outcomes occur swiftly. Recent studies unveiled the immunomodulatory properties SGLT2 inhibitors, shedding light on potential influence immune system inflammation. This comprehensive review explores current state knowledge regarding impact inflammation, focusing preclinical clinical evidence. The delves into anti-inflammatory immune-modulating effects, offering insights implications exploring emerging research areas related prospective impact.

Language: Английский

Citations

10