Dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats

Jaikumkao, Krit; Pongchaidecha, Anchalee; Chueakula, Nuttawud; Thongnak, Laongdao; Wanchai, Keerati; Chatsudthipong, Varanuj; Chattipakorn, Nipon; Lungkaphin, Anusorn

doi:10.1111/dom.13441

Cited by 87 publications

(61 citation statements)

References 73 publications

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“…Reports of SGLT1 protein [80,84,103] and mRNA [83-85, 92, 93, 98] contents in PTs of T1D murine models are also contradictory while in T2D models only mRNA expression seems to be upregulated [22,90,92,98,100,[103][104][105][106]. SGLT2 has been studied in many models of diabetes, and the results suggest increased protein [32,67,84,85,90,94,99,[107][108][109][110][111] and mRNA [22,32,83,85,100,104,[106][107][108][109]112] contents and activity [108] despite some controversial results [85,93,98,100,105,113].…”

Section: Tubular Glucose Transporters In Animal Models Ofmentioning

confidence: 99%

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Moreira

Muscelli

2020

Journal of Diabetes Research

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Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.

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Section: Tubular Glucose Transporters In Animal Models Ofmentioning

confidence: 99%

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Moreira

Muscelli

2020

Journal of Diabetes Research

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“…Intriguingly, a recent study reported that the HFD‐fed medaka exhibited enlarged glomeruli, dilated glomerular capillaries, and expanded mesangium, changes comparable to changes observed in humans with metabolic syndrome‐related glomerulopathy . To date, only a few studies demonstrated the beneficial effect of SGLT2Is on chronic renal injury in NASH animal models and elucidated the underlying mechanisms . The mechanisms include the renal inflammation, fibrosis, ER stress, apoptosis and lipid accumulation due to the increased renal expression of reactive oxygen species related to oxidative stress and TGF‐β1, type IV collagen, and fibronectin .…”

mentioning

confidence: 96%

Inhibition of sodium‐glucose cotransporter 2 ameliorates renal injury in a novel medaka model of nonalcoholic steatohepatitis‐related kidney disease

et al. 2019

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The effect of sodium‐glucose cotransporter 2 inhibitor (SGLT2I) on nonalcoholic steatohepatitis (NASH) has been reported, but there are few studies on its effect on NASH‐related renal injury. In this study, we examined the effect of SGLT2I using a novel medaka fish model of NASH‐related kidney disease, which was developed by feeding the d‐rR/Tokyo strain a high‐fat diet. SGLT2I was administered by dissolving it in water of the feeding tank. SGLT2I ameliorates macrophage accumulation and oxidative stress and maintained mitochondrial function in the kidney. The results demonstrate the effect of SGLT2I on NASH‐related renal injury and the usefulness of this novel animal model for research into NASH‐related complications.

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“…Dapagliflozin is the first SGLT2 inhibitor used for anti-hyperglycemia therapy licensed by the FDA in 2014 ( Meng et al., 2008 ; Saeed and Narendran, 2014 ). Besides lowering blood glucose, dapagliflozin has protective roles in diabetic renal function by suppressing apoptosis, inflammation, and endoplasmic reticulum (ER) stress ( Jaikumkao et al., 2018 ). Intriguingly, a previous study revealed the ability of dapagliflozin to induce HIF-1α expression in renal cells ( Chang et al., 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Dapagliflozin Promotes Neovascularization by Improving Paracrine Function of Skeletal Muscle Cells in Diabetic Hindlimb Ischemia Mice Through PHD2/HIF-1α Axis

Nugrahaningrum

Marcelina²,

Liu³

et al. 2020

Front. Pharmacol.

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Diabetes mellitus is associated with a high risk of hindlimb ischemia (HLI) progression and an inevitably poor prognosis, including worse limb salvage and mortality. Skeletal muscle cells can secrete angiogenic factors, which could promote neovascularization and blood perfusion recovery. Thus, paracrine function of skeletal muscle cells, which is aberrant in diabetic conditions, is crucial for therapeutic angiogenesis in diabetic HLI. Dapagliflozin is a well-known anti-hyperglycemia and anti-obesity drug; however, its role in therapeutic angiogenesis is unknown. Herein, we found that dapagliflozin could act as an angiogenesis stimulator in diabetic HLI. We showed that dapagliflozin enhances the viability, proliferation, and migration potentials of skeletal muscle cells and promotes the secretion of multiple angiogenic factors from skeletal muscle cells, most plausibly through PHD2/HIF-1a axis. Furthermore, we demonstrated that conditioned medium from dapagliflozin-treated skeletal muscle cells enhances the proliferation and migration potentials of vascular endothelial and smooth muscle cells, which are two fundamental cells of functional mature vessels. Finally, an in vivo study demonstrated that intramuscular administration of dapagliflozin effectively enhances the formation of mature blood vessels and, subsequently, blood perfusion recovery in diabetic HLI mice. Hence, our results suggest a novel function of dapagliflozin as a potential therapeutic angiogenesis agent for diabetic HLI.

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Dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats

Abstract: Collectively, these findings indicate that dapagliflozin exerts renoprotective effects by alleviating obesity-induced renal inflammation, fibrosis, ER stress, apoptosis and lipid accumulation in the prediabetic condition.

Cited by 87 publications

References 73 publications

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Inhibition of sodium‐glucose cotransporter 2 ameliorates renal injury in a novel medaka model of nonalcoholic steatohepatitis‐related kidney disease

Dapagliflozin Promotes Neovascularization by Improving Paracrine Function of Skeletal Muscle Cells in Diabetic Hindlimb Ischemia Mice Through PHD2/HIF-1α Axis

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