SGLT2 inhibition for cardiovascular diseases, chronic kidney disease and NAFLD

Endocrinology ◽  
2021 ◽  
Author(s):  
Moein Ala
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Observational Studies ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Renal Diseases ◽  
Beneficial Effects

Abstract Sodium glucose cotransporter 2 (SGLT-2) inhibitors are the latest class of anti-diabetic medications. They prevent glucose reabsorption in the proximal convoluted tubule to decrease blood sugar. Several animal studies revealed that SGLT-2 is profoundly involved in the inflammatory response, fibrogenesis and regulation of numerous intracellular signaling pathways. Likewise, SGLT-2 inhibitors markedly attenuated inflammation and fibrogenesis and improved the function of damaged organ in animal studies, observational studies and clinical trials. SGLT-2 inhibitors can decrease blood pressure and ameliorate hypertriglyceridemia and obesity. Likewise, they improve the outcome of cardiovascular diseases such as heart failure, arrhythmias and ischemic heart disease. SGLT-2 inhibitors are associated with lower cardiovascular and all-cause mortality, as well. Meanwhile, they protect against non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), acute kidney injury (AKI), and improve micro- and macroalbuminuria. SGLT-2 inhibitors can reprogram numerous signaling pathways to improve NAFLD, cardiovascular diseases and renal diseases. For instance, they enhance lipolysis, ketogenesis, mitochondrial biogenesis and autophagy while they attenuate renin-angiotensin-aldosterone system (RAAS), lipogenesis, endoplasmic reticulum (ER) stress, oxidative stress, apoptosis and fibrogenesis. This review explains the beneficial effects of SGLT-2 inhibitors on NAFLD, cardiovascular and renal diseases and dissects the underlying molecular mechanisms in detail. This narrative review explains the beneficial effects of SGLT-2 inhibitors on NAFLD, cardiovascular and renal diseases using the results of latest observational studies, clinical trials and meta-analyses. Thereafter, it dissects the underlying molecular mechanisms involved in the clinical effects of SGLT-2 inhibitors on these diseases.

scholarly journals Effects and Mechanisms of Tea Regulating Blood Pressure: Evidences and Promises

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1115 ◽  
Author(s):  
Daxiang Li ◽  
Ruru Wang ◽  
Jinbao Huang ◽  
Qingshuang Cai ◽  
Chung S. Yang ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Animal Studies ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Vascular Inflammation ◽  
Optimal Dose ◽  
Smooth Muscle Contraction ◽  
Beneficial Effects ◽  
Underlying Mechanisms

Cardiovascular diseases have overtaken cancers as the number one cause of death. Hypertension is the most dangerous factor linked to deaths caused by cardiovascular diseases. Many researchers have reported that tea has anti-hypertensive effects in animals and humans. The aim of this review is to update the information on the anti-hypertensive effects of tea in human interventions and animal studies, and to summarize the underlying mechanisms, based on ex-vivo tissue and cell culture data. During recent years, an increasing number of human population studies have confirmed the beneficial effects of tea on hypertension. However, the optimal dose has not yet been established owing to differences in the extent of hypertension, and complicated social and genetic backgrounds of populations. Therefore, further large-scale investigations with longer terms of observation and tighter controls are needed to define optimal doses in subjects with varying degrees of hypertensive risk factors, and to determine differences in beneficial effects amongst diverse populations. Moreover, data from laboratory studies have shown that tea and its secondary metabolites have important roles in relaxing smooth muscle contraction, enhancing endothelial nitric oxide synthase activity, reducing vascular inflammation, inhibiting rennin activity, and anti-vascular oxidative stress. However, the exact molecular mechanisms of these activities remain to be elucidated.

scholarly journals The Use of Chinese Yang/Qi-Invigorating Tonic Botanical Drugs/Herbal Formulations in Ameliorating Chronic Kidney Disease by Enhancing Mitochondrial Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiayi Tian ◽  
Yuqi Huang ◽  
Tong Wu ◽  
Hsien-Da Huang ◽  
Kam Ming Ko ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mitochondrial Function ◽  
Antioxidant Status ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mitochondrial Energy Metabolism ◽  
Beneficial Effects ◽  
Mitochondrial Functions ◽  
Herbal Formulations

Background: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Mitochondrial dysfunction has been implicated as a key factor in the development of CKD. According to traditional Chinese medicine (TCM) theory, many Chinese Yang/Qi-invigorating botanical drugs/herbal formulations have been shown to produce promising outcomes in the clinical management of CKD. Experimental studies have indicated that the health-promoting action of Yang/Qi invigoration in TCM is related to the up-regulation of mitochondrial energy generation and antioxidant status.Objective: In this review, we aim to test whether Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations can provide medical benefits in CKD and its complications. And we also explore the possible involvement of mitochondrial-associated signaling pathway underlying the beneficial effects of Yang/Qi invigoration in TCM.Methods: A systematic search of “PubMed”, “China National Knowledge Infrastructure (CNKI)” and “Google Scholar” was carried out to collect all the available articles in English or Chinese related to Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations and their effects on mitochondrial function and chronic kidney disease.Result and Discussion: The relationship between the progression of CKD and mitochondrial function is discussed. The effects of Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations and their active ingredients, including phytosterols/triterpenes, flavonoids, and dibenzocyclooctadiene lignans, on CKD and related alterations in mitochondrial signaling pathways are also presented in this review. In the future, exploration of the possible beneficial effects and clinical studies of more Yang- and Qi-invigorating botanical drugs/herbal formulations in the prevention and/or/treatment of CKD and the molecular mechanisms relating to the enhancement of mitochondrial functions warrants further investigation.Conclusion: Given the critical role of mitochondrial function in safeguarding renal functional integrity, the enhancement of mitochondrial energy metabolism and antioxidant status in kidney tissue is likely involved in renal protection. Future studies on the biochemical and chemical basis underlying the effects of Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations from a mitochondrial perspective will hopefully provide novel insights into the rational development of new drugs for the prevention and/or treatment of CKD.

scholarly journals Mechanisms and Efficacy of Chinese Herbal Medicines in Chronic Kidney Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Mingming Zhao ◽  
Yi Yu ◽  
Rumeng Wang ◽  
Meiying Chang ◽  
Sijia Ma ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Trials ◽  
Kidney Disease ◽  
Molecular Mechanisms ◽  
Herbal Medicines ◽  
Small Sample ◽  
Chinese Herbal Medicines ◽  
Chinese Herbal ◽  
Anti Inflammatory ◽  
Meta Analyses

As the current treatment of chronic kidney disease (CKD) is limited, it is necessary to seek more effective and safer treatment methods, such as Chinese herbal medicines (CHMs). In order to clarify the modern theoretical basis and molecular mechanisms of CHMs, we reviewed the knowledge based on publications in peer-reviewed English-language journals, focusing on the anti-inflammatory, antioxidative, anti-apoptotic, autophagy-mediated and antifibrotic effects of CHMs commonly used in kidney disease. We also discussed recently published clinical trials and meta-analyses in this field. Based on recent studies regarding the mechanisms of kidney disease in vivo and in vitro, CHMs have anti-inflammatory, antioxidative, anti-apoptotic, autophagy-mediated, and antifibrotic effects. Several well-designed randomized controlled trials (RCTs) and meta-analyses demonstrated that the use of CHMs as an adjuvant to conventional medicines may benefit patients with CKD. Unknown active ingredients, low quality and small sample sizes of some clinical trials, and the safety of CHMs have restricted the development of CHMs. CHMs is a potential method in the treatment of CKD. Further study on the mechanism and well-conducted RCTs are urgently needed to evaluate the efficacy and safety of CHMs.

scholarly journals Connexin 43: a New Therapeutic Target Against Chronic Kidney Disease

2018 ◽  
Vol 49 (3) ◽  
pp. 998-1009 ◽  
Author(s):  
Niki Prakoura ◽  
Panagiotis Kavvadas ◽  
Christos E.  Chadjichristos
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Animal Models ◽  
Renal Disease ◽  
Connexin 43 ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Kidney Diseases ◽  
In Vivo Studies ◽  
Renal Diseases

Chronic kidney disease is an incurable to date pathology with a continuously growing incidence that contributes to the increase of the number of deaths worldwide. With currently no efficient prognostic or therapeutic options being available, the only possibility for treatment of end-stage renal disease is renal replacement therapy through dialysis or transplantation. Understanding the molecular mechanisms participating in the progression of renal diseases and uncovering the pathways implicated will permit the identification of novel and more efficient targets of therapy. Connexin43 was recently identified as a novel player in the development of chronic kidney disease. It was found de novo expressed and/or differentially localized in various renal cell populations during progression of renal disease, indicating an abnormal connexin signaling, both in patients and animal models. Subsequent in vivo studies demonstrated that connexin43 is involved in mediating inflammatory and fibrotic processes contributing to renal damage. Genetic, pharmaco-genetic or peptide-based inhibition of connexin43 in animal models and cell culture systems was successful in preventing the progression of the pathology and preserving the cell phenotypes. This review will summarize the recent advances on connexin43 in the field of kidney diseases and discuss the potential of future connexin43-based therapies against chronic kidney disease.

scholarly journals Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9221
Author(s):  
Hidekatsu Yanai ◽  
Hiroki Adachi ◽  
Mariko Hakoshima ◽  
Hisayuki Katsuyama
Keyword(s):  
Metabolic Syndrome ◽  
Chronic Kidney Disease ◽  
Cardiovascular Diseases ◽  
Kidney Disease ◽  
Glucose Transporter ◽  
Dominant Role ◽  
Gouty Arthritis ◽  
Renin Angiotensin System ◽  
Renal Diseases ◽  
The Metabolic Syndrome

Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.

Insulin resistance in chronic kidney disease: a systematic review

2016 ◽  
Vol 311 (6) ◽  
pp. F1087-F1108 ◽  
Author(s):  
Belinda Spoto ◽  
Anna Pisano ◽  
Carmine Zoccali
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Left Ventricular ◽  
Renal Diseases ◽  
Cv Disease ◽  
End Stage

Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.

scholarly journals The Green Tea Polyphenol(—)-epigallocatechin-3-gallate and its beneficial roles in chronic kidney disease

2016 ◽  
Vol 4 (3) ◽  
pp. 99-103 ◽  
Author(s):  
Hui Bao ◽  
Ai Peng
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Green Tea ◽  
Molecular Mechanisms ◽  
Mitochondrial Pathway ◽  
Health Concern ◽  
Renal Diseases ◽  
Nrf2 Signaling Pathway ◽  
Green Tea Polyphenol ◽  
Tea Extract

Abstract Chronic kidney disease (CKD), a condition that affects around 10% of the population, has become a significant public health concern. Current therapeutic strategies to slow down the progression of CKD remain limited. Thus, it is urgent to develop new strategies to manage the patients with CKD. Work within the past decade has improved our understanding of the mechanisms contributing to CKD. In particular, oxidative stress as well as inflammation appears to play a pivotal role in CKD progression. (一)-Epigallocatechin-3-gallate (EGCG), the major catechin of green tea extract, is known as a powerful antioxidant and reactive oxygen species scavenger. Various studies have shown EGCG has a potential role in chronic kidney disease models. It is suggested that EGCG modulates cellular and molecular mechanisms via inflammation-related NF-кB and Nrf2 signaling pathway, as well as apoptosis-related ER stress pathway and mitochondrial pathway. Therefore, based on these studies, this review attempts to present a recent state of our knowledge and understanding of mechanisms of its role on the process of CKD, with the aim of providing some clues for the future optimization of EGCG in renal diseases.

scholarly journals Proinflammatory adipokines and cytokines in abdominal obesity as a factor in the development of atherosclerosis and renal pathology

2022 ◽  
Vol 17 (4) ◽  
pp. 101-110
Author(s):  
E. A. Ryabova ◽  
I. Y. Ragino
Keyword(s):  
Chronic Kidney Disease ◽  
Adipose Tissue ◽  
Kidney Disease ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Overweight And Obesity ◽  
Renal Diseases ◽  
Pubmed Database ◽  
Wide Range ◽  
Pro Inflammatory Cytokines

In recent decades, there has been an increase in the prevalence of overweight and obesity. Obesity has become an underestimated pandemic and a public health threat around the world. Adipose tissue is positioned as an endocrine organ that secretes a wide range of pro-inflammatory cytokines and adipokines, inducing a state of chronic subinflammation. The results of epidemiological studies over the past 30 years have also shown that visceral adipose tissue is an independent risk factor for the development of atherosclerosis, cardiometabolic diseases and chronic kidney disease. We performed a systematic review to summarize important aspects of the state of chronic subinflammation in the context of its effect on the decrease in glomerular filtration rate and the development of chronic kidney disease. The review deals with the etiology and pathogenesis of obesity, the hormonal profile of adipose tissue, the molecular mechanisms of the effect of pro-inflammatory cytokines and adipokines on the kidneys, and the pathophysiology of renal diseases. Information on the topic from publications based on the Pubmed database has been used.

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