Mitochondrial dysfunction in diabetic kidney disease

Wei, Pascal Zhongping; Szeto, Cheuk Chun

doi:10.1016/j.cca.2019.07.005

Cited by 157 publications

(142 citation statements)

References 139 publications

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“…Proximal renal tubules are the most energy-consuming tissues for sodium/protein reabsorption in the kidney, and contain a great number of mitochondria to carry out ATP production [2,38,41]. It is well known that mitochondrial superoxide production mediated by long-term hyperglycemia leads to mitochondrial dysfunction in proximal renal tubules, and persistent mitochondrial failure plays a critical role in the progression of diabetic nephropathy [36,39]. Under normal physiological conditions, damaged mitochondria are degraded by the autophagy-lysosome system, one of the cytoplasmic ingredients in intracellular protein catabolism [1,4,24].…”

Section: Discussionmentioning

confidence: 99%

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney

Haraguchi

Kohara

Matsubayashi

et al. 2020

Acta Histochem. Cytochem.

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Diabetic nephropathy is a major source of end-stage renal failure, affecting about one-third cases of diabetes mellitus. It has long been accepted that diabetic nephropathy is mainly characterized by glomerular defects, while clinical observations have implied that renal tubular damage is closely linked to kidney dysfunction at the early stages of diabetic nephropathy. In this study, we conducted pathohistological analyses focusing on renal tubular lesions in the early-stage diabetic kidney with the use of a streptozotocin (STZ)induced diabetes mellitus mouse model. The results revealed that histological alterations in renal tubules, shown by a vacuolar nucleic structure, accumulations of PAS-positive substance, and accelerated restoration stress, occur initially without the presence of glomerular lesions in the early-stage diabetic kidney, and that these tubular defects are localized mainly in proximal renal tubules. Moreover, enhanced expression of RAGE, suggesting an aberrant activation of AGEs-RAGE signaling pathway, and accumulation of oxidative modified mitochondria through the impaired autophagy/lysosome system, were also seen in the damaged diabetic proximal renal tubules. Our findings indicate that proximal tubular defects are the initial pathological events increasingly linked to the progression of diabetic nephropathy, and that controlling renal tubular damage could be an effective therapeutic strategy for the clinical treatment of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney

Haraguchi

Kohara

Matsubayashi

et al. 2020

Acta Histochem. Cytochem.

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“…Alterations in mitochondria function determine the intracellular accumulation of lipids and further lipotoxic actions, as reported in both glomeruli and tubules [159][160][161]. The proximal tubule has highly specialized metabolic machinery, which needs a fine energy balance.…”

Section: Mitochondria As the Main Target Of Lipotoxicity-kidney Diseasementioning

confidence: 99%

“…The suppression of β-oxidation described in the DN and advanced CKD patients could be one of the mechanisms that exacerbate the accumulation of lipid drops at the mitochondrial level [161][162][163]. This event turns out to promote the loss of cristae structure, with degeneration and mitochondrial swelling, preventing optimal energetic functioning in different renal cell types [159]. Structural mitochondrial integrity is necessary for the proper functioning of the oxidative phosphorylation and production of ATP [164].…”

Section: Mitochondria As the Main Target Of Lipotoxicity-kidney Diseasementioning

confidence: 99%

“…Recent studies have highlighted the renoprotective role of cardiolipin, a unique phospholipid present in the mitochondrial inner membrane, necessary for the formation and maintenance of mitochondrial cristae structure [158,159,165]. The prevention of cardiolipin peroxidation improves the efficiency of ATP production through the oxidative phosphorylation (OXPHOS) process, restoring mitochondrial bioenergetics [160,161].…”

Section: Mitochondria As the Main Target Of Lipotoxicity-kidney Diseasementioning

confidence: 99%

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Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

189

147

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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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“…4). These findings likely indicate that increases in AQP- According to mitochondrial function and its architecture, mitochondrial dysfunction is a crucial factor in the pathogenesis of diabetic kidney diseases regarding reactive oxygen species overproduction, apoptosis activation and mitophagy defects [28][29][30][31][32][33][34]. The kidney is an extreme oxygen consumption organ, which renders it sensitive to mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 91%

Streptozotocin induces alpha-2u globulin nephropathy in male rats during the end-stage of diabetic kidney disease

Kengkoom¹,

Angkhasirisap²,

Kanjanapruthipong³

et al. 2020

Preprint

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Background Alpha-2u globulin nephropathy mainly shows toxicological pathology only in male rats induced by certain chemicals and drugs, such as levamisole (antiparasitic and anticancer drugs). Streptozotocin (STZ) is also an anticancer-antibiotic agent that has been used for decades to induce a diabetic kidney disease model in rodents. The purpose of this study is to determine if STZ causes alpha-2u globulin nephropathy in male rats during an advanced stage of diabetic kidney disease. Methods To prove this hypothesis, the present study used a male diabetic Wistar rat model with 45 mg/kg of STZ injected intraperitoneally. Hyperglycaemic rats were divided into 2 groups: with and without end-stage kidney disease. Alpha-2u globulin nephropathy was examined by histopathological and electron microscope studies. Water absorption and filtration capacities (via aquaporin [AQP]-1, -2, -4 and -5) and mitochondrial function (through haloacid dehalogenase-like hydrolase domain-containing protein [HDHD]-3 and NADH-ubiquinone oxidoreductase 75 kDa subunit [NDUFS]-1 proteins) were determined using immunohistochemistry, immunofluorescence and immunogold labelling techniques. Results More than 80% of end-stage diabetic kidney disease induced by STZ injection simultaneously exhibited alpha-2u globulin nephropathy with mitochondrial degeneration and filtration apparatus especially pedicels impairment. They also showed significantly upregulated AQP-1, -2, -4 and -5, HDHD-3 and NDUFS-1 compared with those of the rats without alpha-2u globulin nephropathy. Conclusions STZ-induced alpha-2u globulin nephropathy during end-stage diabetic kidney disease in association with deterioration of renal filtration, renal tubular damage with adaptation and mitochondrial apoptosis.

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Mitochondrial dysfunction in diabetic kidney disease

Cited by 157 publications

References 139 publications

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Streptozotocin induces alpha-2u globulin nephropathy in male rats during the end-stage of diabetic kidney disease

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