Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review

Shakour, Neda; Karami, Shima; Iranshahi, Mehrdad; Butler, Alexandra E.; Sahebkar, Amirhossein

doi:10.1016/j.dsx.2023.102934

Cited by 8 publications

(4 citation statements)

References 322 publications

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“…Oxidative stress is associated with the activation of pro-fibrotic pathways in the kidney, leading to the deposition of extracellular matrix proteins, tissue remodeling and, ultimately, renal sclerosis in DKD [9,11,15,[62][63][64][65][66][67][68][69][70][71]. In order to examine the effect of EC-NOX5 expression on pathological pathways causing renal injury, this study examined mesangial expansion, glomerulosclerosis, and markers of extracellular matrix genes and proteins, specifically collagen IV and fibronectin.…”

Section: Discussionmentioning

confidence: 99%

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Jandeleit-Dahm,

Kankanamalage,

Dai

et al. 2024

Antioxidants

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Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Jandeleit-Dahm,

Kankanamalage,

Dai

et al. 2024

Antioxidants

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“…In animal models, SGLT2 inhibitors demonstrate effects on TGF-β-mediated fibrosis, including in murine models with cardiac fibrosis induced by angiotensin II infusion [ 142 ] or diabetes [ 143 ]. The precise mechanisms are poorly understood but may be mediated by indirect effects through dampening the RAAS system and inflammation [ 144 , 145 ]. Studies in preclinical models have also indicated anti-fibrotic effects of neprilysin inhibition.…”

Section: Modest Anti-fibrotic Effects Of Other Heart Failure Drugsmentioning

confidence: 99%

Hitting the Target! Challenges and Opportunities for TGF-β Inhibition for the Treatment of Cardiac fibrosis

Vistnes

2024

Pharmaceuticals

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Developing effective anti-fibrotic therapies for heart diseases holds the potential to address unmet needs in several cardiac conditions, including heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, and cardiotoxicity induced by cancer therapy. The inhibition of the primary fibrotic regulator, transforming growth factor (TGF) β, represents an efficient strategy for mitigating fibrosis in preclinical models. However, translating these findings into clinical benefits faces challenges due to potential adverse effects stemming from TGF-β’s physiological actions in inflammation and tissue homeostasis. Various strategies exist for inhibiting TGF-β, each associated with a distinct risk of adverse effects. Targeting TGF-β directly or through its signaling pathway proves efficient in reducing fibrosis. However, direct TGF-β blockade may lead to uncontrolled inflammation, especially following myocardial infarction, while interference with the signaling pathway may compromise structural integrity, resulting in issues like insufficient wound healing or ventricular dilatation. Influencing TGF-β activity through interacting signaling pathways, for instance by inhibitors of the renin–angiotensin–aldosterone-system, is insufficiently potent in reducing fibrosis. Targeting activators of latent TGF-β, including ADAMTS enzymes, thrombospondin, and integrins, emerges as a potentially safer strategy to reduce TGF-β-induced fibrosis but it requires the identification of appropriate targets. Encouragement is drawn from promising agents developed for fibrosis in other organs, fueling hope for similar breakthroughs in treating cardiac fibrosis. Such advances depend on overcoming obstacles for the implementation of anti-fibrotic strategies in patients with heart disease, including fibrosis quantification. In this review, insights garnered from interventional and mechanistic studies, obtained through a non-systemic search spanning preclinical and clinical evidence, are summarized to pinpoint the most promising targets for further exploration and development.

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“…It has been demonstrated that SGLT2 inhibitors have antifibrotic effects in the kidneys, which contributes to their renoprotective qualities [38]. The therapeutic effect of SGLT2 inhibitors on renal fibrosis may be achieved through multiple pathways regulation, but they are not fully understood [39]. In trials, SGLT2 inhibitors have been shown to reduce inflammatory markers such as IL-6, TNF, IFN-γ, NF-κβ, TLR-4, and TGF-β, increase mitochondrial function, and limit mesangial and myofibroblast growth [34,40].…”

Section: Sglt2 Inhibitors Their Mechanism Of Action and Effects On Ki...mentioning

confidence: 99%

SGLT2 Inhibitors in Kidney Diseases—A Narrative Review

Gajewska,

Wasiak,

Sapeda

et al. 2024

IJMS

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Some of the most common conditions affecting people are kidney diseases. Among them, we distinguish chronic kidney disease and acute kidney injury. Both entities pose serious health risks, so new drugs are still being sought to treat and prevent them. In recent years, such a role has begun to be assigned to sodium-glucose cotransporter-2 (SGLT2) inhibitors. They increase the amount of glucose excreted in the urine. For this reason, they are currently used as a first-line drug in type 2 diabetes mellitus. Due to their demonstrated cardioprotective effect, they are also used in heart failure treatment. As for the renal effects of SGLT2 inhibitors, they reduce intraglomerular pressure and decrease albuminuria. This results in a slower decline in glomelular filtration rate (GFR) in patients with kidney disease. In addition, these drugs have anti-inflammatory and antifibrotic effects. In the following article, we review the evidence for the effectiveness of this group of drugs in kidney disease and their nephroprotective effect. Further research is still needed, but meta-analyses indicate SGLT2 inhibitors' efficacy in kidney disease, especially the one caused by diabetes. Development of new drugs and clinical trials on specific patient subgroups will further refine their nephroprotective effects.

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Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review

Cited by 8 publications

References 322 publications

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Hitting the Target! Challenges and Opportunities for TGF-β Inhibition for the Treatment of Cardiac fibrosis

SGLT2 Inhibitors in Kidney Diseases—A Narrative Review

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