Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition

Das, Nitin A.; Carpenter, Andrea J.; Belenchia, Anthony; Aroor, Annayya R.; Noda, Makoto; Siebenlist, Ulrich; Chandrasekar, Bysani; DeMarco, Vincent G.

doi:10.1016/j.cellsig.2019.109506

Cited by 70 publications

(56 citation statements)

References 58 publications

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“…The SGLT2-Is canagliflozin and empagliflozin reduced the risk of developing fatal and nonfatal CV events in previous trials, with this effect being associated with a reduction of albuminuria in the first 3 to 6 months of treatment [104,105]. However, an interesting recent analysis of human proximal tubular epithelial cells showed that empagliflozin is also able to reverse the renal suppression of Reversion Inducing Cysteine Rich Protein with Kazal Motifs (RECK), a membrane anchored endogenous MMP inhibitor whose expression is induced by hyperglycemia in animal and human models of diabetic kidney disease [106]. Interestingly, empagliflozin reduced the epithelial-to-mesenchymal transition, a mechanism that is strictly linked to MMPs activity and that anticipates kidney fibrosis, by directly reducing migration of tubular cells and expression of pro-inflammatory mediators (TRAF3IP2, NF-κB, p38MAPK, miR-21, and IL-1β, IL-6, TNF-α, and MCP-1).…”

Section: Discussionmentioning

confidence: 99%

The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

et al. 2020

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Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles.

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Section: Discussionmentioning

confidence: 99%

The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

et al. 2020

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“…A similar effect was observed in diabetic CKD patients who underwent treatment with doxycycline, an antibiotic from the tetracycline family, and who were already treated with renin-angiotensin-aldosterone inhibitors (RAAS-i) [103]. Moreover, MMPs are also involved in the mechanism that leads to CV risk reduction exerted by sodium-glucose cotransporter 2 inhibitors (SGLT2-i) through the activation of RECK (reversion-inducing cysteine-rich protein with kazal motifs), an endogenous inhibitor of MMPs [104]. That mechanism appeared to be independent of proteinuria levels and could also be useful for selecting high-risk normoalbuminuric CKD patients to be enrolled in future clinical trials, who represent a non-trivial proportion of the CKD cohort [21].…”

Section: Biomarkers Of Tissue Remodelingmentioning

confidence: 99%

“…MMPs levels are modified by selective and nonselective drugs. Changes in MMP levels are associated with a reduction of CV risk[102][103][104].…”

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confidence: 99%

Contribution of Predictive and Prognostic Biomarkers to Clinical Research on Chronic Kidney Disease

Provenzano

Rotundo

Chiodini

et al. 2020

IJMS

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Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.

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“…We have previously shown that (1) engagement of RAGE with glycer-AGEs evokes inflammatory, thrombogenic, and fibrotic reactions in human renal proximal tubular cells via ROS generation, (2) sodium-glucose cotransporter 2 (SGLT2)-mediated, high glucose-induced ROS generation augments the glycer-AGE-induced apoptotic cell death of proximal tubular cells via RAGE induction, and (3) inhibitors of SGLT2, such as empagliflozin and tofogliflozin, protect against proximal tubular injury in diabetic animals through its anti-oxidative, anti-inflammatory and anti-fibrotic properties via inhibition of the glycer-AGE-RAGE axis [6,[13][14][15][16]. Furthermore, recently, high glucose or AGEs have been shown to promote human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition via oxidative stress generation, all of which were ameliorated by empagliflozin [17]. In addition, an SGLT2 inhibitor, dapagliflozin, inhibited the high glucose-induced inflammatory and fibrotic reactions in human proximal tubular epithelial cells by suppressing the RAGE-downstream signaling pathway [18].…”

Section: Discussionmentioning

confidence: 99%

Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction

Sotokawauchi

Nakamura

Matsui

et al. 2020

IJMS

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Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) contribute to proximal tubulopathy in diabetes. However, what glycer-AGE structure could evoke tubular cell damage remains unknown. We first examined if deleterious effects of glycer-AGEs on reactive oxygen species (ROS) generation in proximal tubular cells were blocked by DNA-aptamer that could bind to glyceraldehyde-derived pyridinium (GLAP) (GLAP-aptamer), and then investigated whether and how GLAP caused proximal tubular cell injury. GLAP-aptamer and AGE-aptamer raised against glycer-AGEs were prepared using a systemic evolution of ligands by exponential enrichment. The binding affinity of GLAP-aptamer to glycer-AGEs was measured with a bio-layer interferometry. ROS generation was evaluated using fluorescent probes. Gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). GLAP-aptamer bound to glycer-AGEs with a dissociation constant of 7.7 × 10 −5 M. GLAP-aptamer, glycer-AGE-aptamer, or antibodies directed against receptor for glycer-AGEs (RAGE) completely prevented glycer-AGE-or GLAP-induced increase in ROS generation, MCP-1, PAI-1, or RAGE gene expression in tubular cells. Our present results suggest that GLAP is one of the structurally distinct glycer-AGEs, which may mediate oxidative stress and inflammatory reactions in glycer-AGE-exposed tubular cells. Blockade of the interaction of GLAP-RAGE by GLAP-aptamer may be a therapeutic target for proximal tubulopathy in diabetic nephropathy.

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Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition

Cited by 70 publications

References 58 publications

The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

Contribution of Predictive and Prognostic Biomarkers to Clinical Research on Chronic Kidney Disease

Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction

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