Dapagliflozin and metformin in combination ameliorates diabetic nephropathy by suppressing oxidative stress, inflammation, and apoptosis and activating autophagy in diabetic rats

Jaikumkao, Krit; Thongnak, Laongdao; Htun, Khin Thandar; Pengrattanachot, Nattavadee; Phengpol, Nichakorn; Sutthasupha, Prempree; Promsan, Sasivimon; Montha, Napatsorn; Sriburee, Sompong; Kothan, Suchart; Lungkaphin, Anusorn

doi:10.1016/j.bbadis.2023.166912

Cited by 7 publications

(1 citation statement)

References 74 publications

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“…Additionally, dapagliflozin reverses the increased expression of circRNAs in proximal tubular epithelial cells (PTECs) treated with high glucose [278]. Dapagliflozin, whether used as monotherapy or in combination with metformin, was found to be more effective than metformin alone in mitigating renal dysfunction, enhancing renal organic anion transporter 3 expression, and promoting renal autophagy in rats with diabetes mellitus [279]. Notably, dapagliflozin monotherapy displayed superior efficacy in suppressing renal oxidative stress in these rats compared to metformin or the combination treatment.…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease

Wang,

Zhang

2024

Antioxidants

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Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its pathogenesis. DKD is the result of complex interactions between various factors. Oxidative stress is a fundamental factor that can establish a link between hyperglycemia and the vascular complications frequently encountered in diabetes, particularly DKD. It is crucial to recognize the essential and integral role of oxidative stress in the development of diabetic vascular complications, particularly DKD. Hyperglycemia is the primary culprit that can trigger an upsurge in the production of reactive oxygen species (ROS), ultimately sparking oxidative stress. The main endogenous sources of ROS include mitochondrial ROS production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), and lipoxygenase. Under persistent high glucose levels, immune cells, the complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, and the hexosamine pathway are activated. Consequently, the oxidant–antioxidant balance within the body is disrupted, which triggers a series of reactions in various downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor beta/p38-mitogen-activated protein kinase (TGF-β/p38-MAPK), nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. The disease might persist even if strict glucose control is achieved, which can be attributed to epigenetic modifications. The treatment of DKD remains an unresolved issue. Therefore, reducing ROS is an intriguing therapeutic target. The clinical trials have shown that bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can effectively slow down the progression of DKD by reducing oxidative stress. Other antioxidants, including vitamins, lipoic acid, Nox inhibitors, epigenetic regulators, and complement inhibitors, present a promising therapeutic option for the treatment of DKD. In this review, we conduct a thorough assessment of both preclinical studies and current findings from clinical studies that focus on targeted interventions aimed at manipulating these pathways. We aim to provide a comprehensive overview of the current state of research in this area and identify key areas for future exploration.

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Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease

Wang,

Zhang

2024

Antioxidants

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Targeting Autophagy: A Promising Therapeutic Strategy for Diabetes Mellitus and Diabetic Nephropathy

Li,

Xu,

et al. 2024

Diabetes Ther

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Diabetes mellitus (DM) significantly impairs patients’ quality of life, primarily because of its complications, which are the leading cause of mortality among individuals with the disease. Autophagy has emerged as a key process closely associated with DM, including its complications such as diabetic nephropathy (DN). DN is a major complication of DM, contributing significantly to chronic kidney disease and renal failure. The intricate connection between autophagy and DM, including DN, highlights the potential for new therapeutic targets. This review examines the interplay between autophagy and these conditions, aiming to uncover novel approaches to treatment and enhance our understanding of their underlying pathophysiology. It also explores the role of autophagy in maintaining renal homeostasis and its involvement in the development and progression of DM and DN. Furthermore, the review discusses natural compounds that may alleviate these conditions by modulating autophagy.

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