P2X7 siRNA targeted to the kidneys increases klotho and delays the progression of experimental diabetic nephropathy

Rodrigues, Adelson Marçal; Serralha, Robson; Lima, Deyse Y.; Punaro, Giovana Rita; Visoná, Iria; Fernandes, Maria José; Higa, Elisa M S

doi:10.1007/s11302-020-09695-1

Cited by 7 publications

(4 citation statements)

References 40 publications

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“…The down-regulation of Cyp4a14 and P2X7 by siRNA ameliorates diabetic nephropathy. 113,114 Furthermore, CTGF and P2Y12 down-regulation by shRNA ameliorates retinopathy and prevents inflammation in DM treatment. 115,116 However, these therapeutics have some problems such as poor bioavailability of drugs and degradation of siRNA in serum that for improving their efficacy, application of nanostructures is recommended.…”

Section: Diabetes Mellitusmentioning

confidence: 99%

Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications

Ashrafizadeh¹,

Kumar²,

Aref³

et al. 2022

IJN

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Diabetes mellitus (DM) is among the chronic metabolic disorders that its incidence rate has shown an increase in developed and wealthy countries due to lifestyle and obesity. The treatment of DM has always been of interest, and significant effort has been made in this field. Exosomes belong to extracellular vesicles with nanosized features (30-150 nm) that are involved in cell-to-cell communication and preserving homeostasis. The function of exosomes is different based on their cargo, and they may contain lipids, proteins, and nucleic acids. The present review focuses on the application of exosomes in the treatment of DM; both glucose and lipid levels are significantly affected by exosomes, and these nanostructures enhance lipid metabolism and decrease its deposition. Furthermore, exosomes promote glucose metabolism and affect the level of glycolytic enzymes and glucose transporters in DM. Type I DM results from the destruction of β cells in the pancreas, and exosomes can be employed to ameliorate apoptosis and endoplasmic reticulum (ER) stress in these cells. The exosomes have dual functions in mediating insulin resistance/sensitivity, and M1 macrophage-derived exosomes inhibit insulin secretion. The exosomes may contain miRNAs, and by transferring among cells, they can regulate various molecular pathways such as AMPK, PI3K/Akt, and β-catenin to affect DM progression. Noteworthy, exosomes are present in different body fluids such as blood circulation, and they can be employed as biomarkers for the diagnosis of diabetic patients. Future studies should focus on engineering exosomes derived from sources such as mesenchymal stem cells to treat DM as a novel strategy.

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Section: Diabetes Mellitusmentioning

confidence: 99%

Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications

Ashrafizadeh¹,

Kumar²,

Aref³

et al. 2022

IJN

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“…The silencing of P2X 7 receptor demonstrated its kidney deleterious effect as its low expression improved kidney function and balanced oxidative and nitrosative profiles, demonstrating that inhibiting P2X 7 can benefit the kidneys and slow DN progression 43 . In addition, we found that calcium entrance by P2X 7 was intense when DM did not have adjuvant therapy.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we found that calcium entrance by P2X 7 was intense when DM did not have adjuvant therapy. High levels of free calcium in the cytoplasm trigger apoptotic mechanisms manifested by mitochondrial stress, cytochrome c release, and caspase 3 formation, demonstrating that P2X 7 extremely elevates intracellular calcium 43 . It was also observed that the partial absence of P2X 7 modulates the renin-angiotensin system and increases NO levels 44 .…”

Section: Discussionmentioning

confidence: 99%

P2X7 receptor-nitric oxide interaction mediates apoptosis in mouse immortalized mesangial cells exposed to high glucose

et al. 2022

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Introduction: Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia that leads to diabetic nephropathy (DN). We showed that P2X7, a purinergic receptor, was highly expressed in DM; however, when oxidative stress was controlled, renal NO recovered, and the activation of this receptor remained significantly reduced. The aim of this study was to assess the influence of NO on the P2X7 and apoptosis in mouse immortalized mesangial cells (MiMC) cultured in high glucose (HG) medium. Methods: MiMCs were cultured with DMEM and exposed to normal glucose (NG), mannitol (MA), or HG. Cell viability was assessed by an automated counter. Supernatants were collected for NO quantification, and proteins were extracted for analysis of NO synthases (iNOS and eNOS), caspase-3, and P2X7. Results: Cell viability remained above 90% in all groups. There was a significant increase in the proliferation of cells in HG compared to MA and NG. NO, iNOS, caspase-3, and P2X7 were significantly increased in HG compared to NG and MA, with no changes in eNOS. We observed that there was a strong and significant correlation between P2X7 and NO. Discussion: The main finding was that the production of NO by iNOS was positively correlated with the increase of P2X7 in MCs under HG conditions, showing that there is a common stimulus between them and that NO interacts with the P2X7 pathway, contributing to apoptosis in experimental DM. These findings could be relevant to studies of therapeutic targets for the prevention and/or treatment of hyperglycemia-induced kidney damage to delay DN progression.

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“…However, these studies can be limited by the larger size of rats and corresponding increased expenses compared to mice and by the notion that some, perhaps most, of these well-characterized compounds may not be readily available to all researchers due to their clinical potential and testing in people. More recent studies using the local delivery of small interfering RNA to silence P2X7 in rats have revealed a role for this receptor in diabetic neuropathy [256][257][258], epilepsy [259] and intracerebral hemorrhage [260]. This provides alternative therapies to the use of small molecule inhibitors to investigate P2X7 in vivo.…”

Section: Rats 41 Preclinical Rat Modelsmentioning

confidence: 99%

Animal Models for the Investigation of P2X7 Receptors

Sluyter

Adriouch

Fuller

et al. 2023

IJMS

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The P2X7 receptor is a trimeric ligand-gated cation channel activated by extracellular adenosine 5′-triphosphate. The study of animals has greatly advanced the investigation of P2X7 and helped to establish the numerous physiological and pathophysiological roles of this receptor in human health and disease. Following a short overview of the P2X7 distribution, roles and functional properties, this article discusses how animal models have contributed to the generation of P2X7-specific antibodies and nanobodies (including biologics), recombinant receptors and radioligands to study P2X7 as well as to the pharmacokinetic testing of P2X7 antagonists. This article then outlines how mouse and rat models have been used to study P2X7. These sections include discussions on preclinical disease models, polymorphic P2X7 variants, P2X7 knockout mice (including bone marrow chimeras and conditional knockouts), P2X7 reporter mice, humanized P2X7 mice and P2X7 knockout rats. Finally, this article reviews the limited number of studies involving guinea pigs, rabbits, monkeys (rhesus macaques), dogs, cats, zebrafish, and other fish species (seabream, ayu sweetfish, rainbow trout and Japanese flounder) to study P2X7.

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P2X7 siRNA targeted to the kidneys increases klotho and delays the progression of experimental diabetic nephropathy

Cited by 7 publications

References 40 publications

Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications

Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications

P2X7 receptor-nitric oxide interaction mediates apoptosis in mouse immortalized mesangial cells exposed to high glucose

Animal Models for the Investigation of P2X7 Receptors

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