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1.
Int Immunopharmacol ; 131: 111785, 2024 Apr 20.
Article in English | MEDLINE | ID: mdl-38479158

ABSTRACT

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1ß in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.


Subject(s)
Benzhydryl Compounds , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Glucosides , MicroRNAs , Podocytes , Renal Insufficiency , Animals , Mice , Heme Oxygenase-1/genetics , Diabetes Mellitus, Experimental/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Pyroptosis , Kidney , Diabetic Nephropathies/drug therapy , MicroRNAs/genetics
2.
Br J Pharmacol ; 172(2): 630-41, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24866991

ABSTRACT

BACKGROUND AND PURPOSE: Opioid antagonists, such as naloxone and naltrexone, exhibit agonistic properties at the mutated µ receptor, MOR-S196ACSTA. In our previous study, systemic naloxone (10 mg·kg(-1) , s.c.) elicited antinociceptive effect without the induction of tolerance, dependence or rewarding effect in mice 2 weeks after intrathecal administration of double-stranded adeno-associated virus-MOR-S196ACSTA-eGFP. Here, we have investigated if this antinociceptive paradigm would be effective in a mouse model of neuropathic pain. EXPERIMENTAL APPROACH: Spinal nerves were ligated in male C57BL/6 mice 3 or 4 weeks after intrathecal injection of the lentivirus encoding the construct of MOR-S196ACSTA-eGFP (LV-MOR-S196ACSTA). Anti-allodynic effects of daily s.c.injections of saline, naltrexone (10 mg·kg(-1) ) or morphine (10 mg·kg(-1) ) were assessed by the von Frey test. After 14 days of treatment with saline, naltrexone or morphine, signs of natural withdrawal were measured at 22 and 46 h after the last injection. To determine the rewarding effects induced by morphine or naltrexone, the conditioned place preference test was carried out. KEY RESULTS: Anti-allodynic effects, as measured by von Frey test, increased after naltrexone or morphine treatment in mice transfected with LV-MOR-S196ACSTA in the spinal cord. Cessation of treatment with morphine, but not naltrexone, induced natural withdrawal and rewarding effects. CONCLUSIONS AND IMPLICATIONS: Systemic injection of naltrexone after the expression of a mutant µ opioid receptor, MOR-S196ACSTA, in the spinal cord may have therapeutic potential for chronic neuropathic pain, without the development of dependence or addiction. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.


Subject(s)
Analgesics/therapeutic use , Naltrexone/therapeutic use , Narcotic Antagonists/therapeutic use , Neuralgia/drug therapy , Receptors, Opioid, mu/genetics , Analgesics/pharmacology , Animals , Conditioning, Psychological , Genetic Vectors , HEK293 Cells , Humans , Lentivirus/genetics , Male , Mice, Inbred C57BL , Morphine/pharmacology , Morphine/therapeutic use , Mutation , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Neuralgia/metabolism , Receptors, Opioid, mu/metabolism , Reward , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Nerves , Substance Withdrawal Syndrome , Transfection
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