Exendin-4 attenuates renal tubular injury by decreasing oxidative stress and inflammation in streptozotocin-induced diabetic mice

Sancar-Bas, Serap; Gezginci‐Oktayoglu, Selda; Bolkent, Şehnaz

doi:10.3109/08977194.2015.1125349

Cited by 56 publications

(43 citation statements)

References 66 publications

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“…We were able to show that exendin-4 reduces Na + K + ATPase activity, suggesting reduced CSF secretion at the choroid plexus. Previous studies have shown similar effects of exendin-4 on Na + K + ATPase activity in the renal system (34). In kidney proximal tubule epithelial cells and pancreatic b cells, GLP-1 modulates Na + concentration through increased cAMP and PKA activation (18,35).…”

Section: Discussionmentioning

confidence: 61%

A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

et al. 2017

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Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na- and K-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.

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Section: Discussionmentioning

confidence: 61%

A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

et al. 2017

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“…Old studies in diabetes models evaluated the NKA activity in the whole kidney and nephron segments, but not in isolated PTs [147], and were inconclusive. Results of recent studies in the whole kidney are still contradictory [148][149][150][151][152][153][154] probably because of mixed tissue responses and discrepancies in disease duration and glucose levels.…”

Section: Glucose Effects On Renal Glucosementioning

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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“…Ophthalmic Res 2020;63:404-412 DOI: 10.1159/000504891 causes RPE cell dysfunction or apoptosis. GLP-1 receptor agonist can inhibit oxidative stress in some cells, such as pancreatic β cells, myotube, and renal cells [18][19][20]. However, there is no evidence on whether EX4 can reduce oxidative stress-induced RPE cell damage.…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 Protects Human Retinal Pigment Epithelial Cells from H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Damage via Activation of NRF2 Signaling

Cui

Tian

et al. 2019

Ophthalmic Res

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Aims: Oxidative damage plays a vital role in the pathogenesis of age-related macular degeneration (AMD). Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, possesses several pharmacological functions, such as anti-inflammatory and antioxidative properties. However, the effects and mechanism of EX4 on oxidative stress in retinal pigment epithelial (RPE) cells induced by hydrogen peroxide (H 2 O 2) remain unclear. The present study aimed to investigate the protective mechanism of EX4 on human RPE cells subjected to oxidative stress. Methods: Human RPE ARPE-19 cells were treated with H 2 O 2 to induce oxidative damage. Cell viability was determined by Cell Counting Kit-8 and lactate dehydrogenase assay. Levels of intracellular reactive oxygen species (ROS), malonyldialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH) were measured using commercial kits. The expression of nuclear factor erythroid 2-related factor-2 (NRF2), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO-1) was measured using reverse transcription quantitative polymerase chain reaction assay and western blot, respectively. Results: H 2 O 2 significantly induced oxidative stress to reduce viability of RPE cells and increased intracellular ROS generation. EX4 significantly ameliorated H 2 O 2-induced oxidative damage by reducing intracellular ROS generation, decreasing MDA concentration, and increasing antioxidant enzymes activities (SOD and GSH). In addition, EX4 markedly increased expression of NRF2, HO-1, and NQO-1 and significantly improved protein expression of NRF2 and HO-1 in H 2 O 2-treated ARPE-19 cells, caused by increased nuclear NRF2 protein expression. NRF2 knockdown by targeted siRNA alleviated EX4-mediated HO-1 expression and significantly nullified EX4-mediated RPE cell protection against H 2 O 2. Conclusions: EX4 attenuated oxidative damage induced by H 2 O 2 in ARPE-19 cells through the activation of the NRF2 signaling pathway. The findings suggested that EX4 may be a potential therapeutic agent for the treatment of AMD.

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Exendin-4 attenuates renal tubular injury by decreasing oxidative stress and inflammation in streptozotocin-induced diabetic mice

Cited by 56 publications

References 66 publications

A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

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

Exendin-4 Protects Human Retinal Pigment Epithelial Cells from H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Damage via Activation of NRF2 Signaling

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