SGLT2 inhibitor counteracts NLRP3 inflammasome
            <i>via</i>
            tubular metabolite itaconate in fibrosis kidney

Ke, Qingqing; Shi, Caifeng; Lv, Yunhui; Wang, Lulu; Jiang, Lei; Yang, Junwei; Zhou, Yang

doi:10.1096/fj.202100909rr

Cited by 49 publications

(36 citation statements)

References 56 publications

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“…In C57BL/6J mice with renal ischemia/reperfusion injury-induced kidney fibrosis, dapagliflozin decreases de expression of NLRP3 and blocks the activation of IL-1β, IL-18, and caspase-1 in the kidney [ 227 ]. In accordance with this, in BTBR ob/ob mice with diabetic nephropathy, dapagliflozin decreases the expression of NLRP3, TNFα, and caspase-1 in the kidney, along with an increase in AMPK phosphorylation, counteracting the disease progression [ 228 ].…”

Section: Sglt2i and Inflammationmentioning

confidence: 99%

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Feijóo‐Bandín

Aragón-Herrera

Otero-Santiago

et al. 2022

IJMS

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Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.

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Section: Sglt2i and Inflammationmentioning

confidence: 99%

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Feijóo‐Bandín

Aragón-Herrera

Otero-Santiago

et al. 2022

IJMS

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“…The inhibitors block glucose reabsorption in the proximal tubule, increasing glucose excretion in the urine, allowing blood glucose to be controlled without the risk of hypoglycaemia ( Shaffner et al, 2021 ), reducing glomerular hyperfiltration through sodium mediated activation of tubuloglomerular feedback ( Davidson, 2019 ). Dapagliflozin, an SGLT2 inhibitor, has been shown to reduce renal injury even in the absence of diabetes, through inhibition of the NLRP3 inflammasome, protecting against kidney fibrosis ( Ke et al, 2022 ). Unfortunately, whilst SGLT2i represent a major advance in the treatment of diabetic nephropathy, limitations of wide range suitability and potential side effects including diabetic ketoacidosis ( Douros et al, 2020 ), genital infections ( Liu et al, 2017 ) and lower limb amputation ( Neal et al, 2017 ) suggest that they are not a one size fits all, and so other options must also be explored ( Nelinson et al, 2021 ).…”

Section: The Nlrp3 Inflammasomementioning

confidence: 99%

The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy

et al. 2022

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The NOD-like receptor protein 3 (NLRP3) inflammasome is a multi-protein signalling complex integral to the chronic inflammatory response, activated in response to sterile and non-sterile cellular damage. The assembly and activation of the NLRP3 inflammasome comprise a two-step process involving nuclear factor kappa B (NFkB)-mediated priming, followed by canonical, non-canonical or alternative signalling pathways. These result in the maturation and release of inflammatory cytokines interleukin 1 beta (IL1ß) and interleukin-18 (IL18), which are associated with chronic inflammatory conditions including diabetic kidney disease. Diabetic nephropathy is a condition affecting ∼40% of people with diabetes, the key underlying pathology of which is tubulointerstitial inflammation and fibrosis. There is growing evidence to suggest the involvement of the NLRP3 inflammasome in this chronic inflammation. Early deterioration of kidney function begins in the glomerulus, with tubular inflammation dictating the progression of late-stage disease. Priming and activation of the NLRP3 inflammasome have been linked to several clinical markers of nephropathy including proteinuria and albuminuria, in addition to morphological changes including mesangial expansion. Treatment options for diabetic nephropathy are limited, and research that examines the impact of directly targeting the NLRP3 inflammasome, or associated downstream components are beginning to gain favour, with several agents currently in clinical trials. This review will explore a role for NLRP3 inflammasome activation and signalling in mediating inflammation in diabetic nephropathy, specifically in the glomerulus and proximal tubule, before briefly describing the current position of therapeutic research in this field.

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“…It is hypothesized that SGLT2i facilitates lipolysis and ketogenesis by inducing a fasting-like transcriptional paradigm [43,44]. In nondiabetic obese mice, canagliflozin mimics a fasting-like transcriptional paradigm through activation of adenosine monophosphate (AMP)activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) [43,45]. In addition, SGLT2i and the expression of angiotensin II receptor type 1 (AT1R) decreased in diabetic mice treated with dapagliflozin for 12 weeks [60].…”

Section: Hemodynamic Hypothesismentioning

confidence: 99%

“…Dapagliflozin-treated hypertensive mice exhibit reduced blood pressure levels and antisympathetic effects, such as decline in tyrosine hydroxylase and norepinephrine production [59]. Urinary angiotensin Ⅱ and angiotensinogen inhibits NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and fibrosis factor expression in the BTBR ob/ob mice model of T2DM [74] by boosting the tricarboxylic acid (TCA) cycle metabolite itaconate [45]. In mice treated with empagliflozin, microtubule-associated protein 1 light chain 3 (LC3)-Ⅱ/LC3-Ⅰ and bcl2/bax ratios decreased, revealing autophagy activation and apoptosis inhibition [75].…”

Section: Oxidative Stress and Inflammationmentioning

confidence: 99%

Renoprotective mechanisms of SGLT2 inhibitor in diabetic kidney disease

Yan

Wen

Liu

2021

Diabetic Nephropathy

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Diabetic kidney disease (DKD), as the primary cause of end-stage renal disease (ESRD), is becoming a growing public health challenge worldwide. Early intervention in conditions involving high glucose levels will prevent the progression of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) comprise a new class of medications used to reduce hyperglycemia in patients with diabetes by inhibiting renal reabsorption of filtered glucose. Interestingly, SGLT2i is not only capable of controlling the blood glucose level but also has other benefits in terms of blood pressure control, body weight decrease, and albuminuria reduction. It is assumed that various events, such as energy metabolism disorder, insulin resistance, glomerular hyperfiltration, oxidative stress, inflammation, and fibrosis, attributable to the pathogenesis of DKD, can be improved by SGLT2i. Clinical trials have demonstrated that SGLT2i can exert renoprotective effects and reduce the morbidity and mortality due to ESRD. In this review, we focus on the most recent findings from clinical trials and the underlying mechanisms by which SGLT2 inhibitors afford renal protection.

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SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney

Cited by 49 publications

References 56 publications

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy

Renoprotective mechanisms of SGLT2 inhibitor in diabetic kidney disease

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