Insight into the Molecular Mechanism of Diabetic Kidney Disease and the Role of Metformin in Its Pathogenesis

Kleibert, Marcin; Zygmunciak, Przemysław; Łakomska, Klaudia; Mila, Klaudia; Zgliczyński, Wojciech; Mrozikiewicz-Rakowska, Beata

doi:10.3390/ijms241713038

Cited by 4 publications

(4 citation statements)

References 157 publications

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“…The activity of the polyol pathway in the kidney is exceptionally high, with the concentration of enzymes aldose reductase (AR), a key enzyme, peaking in the kidney medulla at 29.3 micrograms per milligram of protein. This elevated activity results in heightened oxidative and osmotic stress in the kidneys [18] (Figure 2), potentially causing damage and disease. The polyol pathway is one of metabolic pathways that converts glucose into sorbitol under the actions of the AR and NADPH.…”

Section: Polyol Pathwaymentioning

confidence: 99%

“…It is noteworthy that this imbalance results in the damage and dysfunction of kidney cells, ultimately leading to the development of DKD. Multiple cytokines, the accumulation of advanced glycation end products (AGEs), and the activated polyol pathway can trigger oxidative stress [18], leading to lesions in the small vessels of the kidney and hastening kidney damage. Hyperglycemia, a primary culprit in the development of DKD, also serves as the primary instigator of renal tubular injury.…”

Section: Introductionmentioning

confidence: 99%

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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: Polyol Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang,

Zhang

2024

Antioxidants

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“…For most patients with T2D and DKD, metformin and SGLT2 inhibitors are recommended as the first-line pharmacologic treatment with eGFR is above 30 mL/min/1.73 m 2 [159]. In addition, metformin has been shown to activate muscle AMPK and promote glucose uptake, reduce ROS production, and delay the progression of DKD [161,162].…”

Section: Metforminmentioning

confidence: 99%

Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

Jha,

Lopez-Trevino,

Kankanamalage

et al. 2024

Biomedicines

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Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.

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“…The main metabolic pathways induced by hyperglycaemia include the polyol pathway, the hexosamine pathway, the protein kinase C (PKC) pathway, and the advanced glycation end products (AGE) pathway. These processes could not only lead to increased ROS production, but also activate inflammatory response, alter gene expression, or induce osmotic and oxidative stress [104].…”

Section: Oxidative Stressmentioning

confidence: 99%

Molecular Processes Involved in the Shared Pathways between Cardiovascular Diseases and Diabetes

Tokarek,

Budny,

Saar

et al. 2023

Biomedicines

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Cardiovascular diseases and diabetes mellitus are currently among the diseases with the highest morbidity and mortality. The pathogenesis and development of these diseases remain strongly connected, along with inflammation playing a major role. Therefore, the treatment possibilities showing a positive impact on both of these diseases could be especially beneficial for patients. SGLT-2 inhibitors and GLP-1 receptor agonists present this dual effect. Moreover, the hostile composition of the gut microbiota could influence the progression of these conditions. In this review, the authors present the latest knowledge on and innovations in diabetes mellitus and CVD—with the focus on the molecular mechanisms and the role of the microbiota.

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Insight into the Molecular Mechanism of Diabetic Kidney Disease and the Role of Metformin in Its Pathogenesis

Cited by 4 publications

References 157 publications

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

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

Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

Molecular Processes Involved in the Shared Pathways between Cardiovascular Diseases and Diabetes

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