Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease

Matoba, Keiichiro; Takeda, Yusuke; Nagai, Yosuke; Yokota, Tamotsu; Utsunomiya, Kazunori; Nishimura, Rimei

doi:10.3390/biomedicines8020040

Cited by 38 publications

(35 citation statements)

References 73 publications

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“…Complete and comprehensive studies not only will shed insights into the mechanisms of DKD but will also facilitate identification of targets that can be explored for DKD therapy. As indicated in a recent review article by Matoba et al [ 243 ], targeting NADH/NAD + redox imbalance would be a valuable approach for combating DKD. Finally, it should be pointed out that in terms of potential injury caused by redox imbalance, which part of the kidney or what type of cells that sustain the most damage have not been comprehensively evaluated.…”

Section: Discussionmentioning

confidence: 99%

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

2021

Biomolecules

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Diabetic kidney disease (DKD) is a common and severe complication of diabetes mellitus. If left untreated, DKD can advance to end stage renal disease that requires either dialysis or kidney replacement. While numerous mechanisms underlie the pathogenesis of DKD, oxidative stress driven by NADH/NAD+ redox imbalance and mitochondrial dysfunction have been thought to be the major pathophysiological mechanism of DKD. In this review, the pathways that increase NADH generation and those that decrease NAD+ levels are overviewed. This is followed by discussion of the consequences of NADH/NAD+ redox imbalance including disruption of mitochondrial homeostasis and function. Approaches that can be applied to counteract DKD are then discussed, which include mitochondria-targeted antioxidants and mimetics of superoxide dismutase, caloric restriction, plant/herbal extracts or their isolated compounds. Finally, the review ends by pointing out that future studies are needed to dissect the role of each pathway involved in NADH-NAD+ metabolism so that novel strategies to restore NADH/NAD+ redox balance in the diabetic kidney could be designed to combat DKD.

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Section: Discussionmentioning

confidence: 99%

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

2021

Biomolecules

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“…In this study, we measured 4-HNE as a marker of oxidative lipid, but other markers of oxidative DNA and protein may strongly support the protective effect of geniposide against oxidative damages induced in diabetic kidney [61]. The redox imbalance in diabetic kidney leads to the development of albuminuria, glomerular and tubular injury, renal hypertrophy, chronic inflammation and interstitial fibrosis [54,55,62]. Consistently, our results suggest that the antioxidant effect of geniposide are associated with a significant reduction in renal apoptosis, inflammation and interstitial fibrosis, ultimately improving renal pathology and function in DN.…”

Section: Discussionmentioning

confidence: 95%

Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation

Dusabimana

Park

et al. 2021

IJMS

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Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.

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“…Hyperglycaemia activates several metabolic pathways, such as polyol pathway, hexosamine pathway, protein kinase C (PKC) pathway, and advanced glycation end-product (AGE)-related pathway, all of which result in the accumulation of reactive oxygen species (ROS). 27 Excessive ROS are also generated by mitochondrial dysfunction and upregulation of pro-oxidant enzymes, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, in diabetic kidneys. 28 ROS oxidize important macromolecules including proteins, lipids, and nucleic acids, which eventually leads to significant tissue damage.…”

Section: Cellular and Molecular Biology Of Dkdmentioning

confidence: 99%

Update on diagnosis, pathophysiology, and management of diabetic kidney disease

et al. 2021

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Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus which may eventually lead to end-stage kidney disease (ESKD). Despite improvements in glycaemic control and blood pressure management with renin-angiotensin-aldosterone system (RAAS) blockade, the current therapy cannot completely halt DKD progression to ESKD in some patients. DKD is a heterogeneous disease entity in terms of its clinical manifestations, histopathology and the rate of progression, which makes it difficult to develop effective therapeutics. It was formerly considered that albuminuria preceded kidney function decline in DKD, but recent epidemiological studies revealed that a distinct group of patients presented kidney dysfunction without developing albuminuria.Other comorbidities, such as hypertension, obesity and gout, also affect the clinical course of DKD. The pathophysiology of DKD is complex and multifactorial, involving both metabolic and haemodynamic factors. These induce activation of intracellular signalling pathways, oxidative stress, hypoxia, dysregulated autophagy and epigenetic changes, which result in kidney inflammation and fibrosis. Recently, two groups of antidiabetic drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, were demonstrated to provide renoprotection on top of their glucose-lowering effects. Several other therapeutic agents are also being developed and evaluated in clinical trials.

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Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease

Cited by 38 publications

References 73 publications

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation

Update on diagnosis, pathophysiology, and management of diabetic kidney disease

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