Impact of high glucose and transforming growth factor–β on bioenergetic profiles in podocytes

Stieger, Nicole; Worthmann, Kirstin; Teng, Beina; Engeli, Stefan; Das, Anibh M.; Haller, Hermann; Schiffer, Mario

doi:10.1016/j.metabol.2011.12.003

Cited by 70 publications

(44 citation statements)

References 40 publications

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“…In light of recent studies indicating that detrimental effects of TGF-b in diabetic nephropathy may be mediated by induction of mitochondrial Nox4 and increased ROS production via activation of TGF-b receptor dependentSmad2/3 signaling, 43,44 we propose that there may exist a vicious cycle, with high glucose directly activating NADPH oxidase-dependent ROS production and subsequent Src kinase-mediated EGFR signaling leading to TGF-b-Smad2/3 activation, which may in turn further activate mitochondrial NADPH oxidase to increase ROS production and Src kinase activity, thereby enhancing TGF-bmediated podocyte injury. …”

Section: Discussionmentioning

confidence: 99%

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Chen¹,

Chen

Harris

2015

Journal of the American Society of Nephrology

115

114

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The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR podKO ) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR podKO mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR podKO diabetic mice had less TGF-b1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR podKO diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-b1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-b1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Chen¹,

Chen

Harris

2015

Journal of the American Society of Nephrology

115

114

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“…As discussed above, oxidative stress, by activating TGF-β1 pathway, is thought to be the major mechanism underlying the pathogenesis of diabetic nephropathy [3,4]. Here, we performed several experiments to probe the effect of Danshen injection on oxidative stress in our model.…”

Section: Danshen Injection Reduced the Level Of Reactive Oxygen Specimentioning

confidence: 98%

“…Increased reactive oxygen species (ROS) can cause vascular endothelium abnormalities and upregulate transforming growth factor (TGF)-β1 and extracellular matrix (ECM) expression to induce fibrosis in DN [4]. Evidence has also shown that anti-oxidants can effectively inhibit high glucose-induced ECM production, such as TGF-β1 and fibronectin [5].…”

Section: Introductionmentioning

confidence: 99%

Danshen injection ameliorates STZ-induced diabetic nephropathy in association with suppression of oxidative stress, pro-inflammatory factors and fibrosis

Shen²,

Bi³

et al. 2016

International Immunopharmacology

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“…PPAR-γ activation ameliorated the mitochondrial dysfunction induced by aldosterone in podocyts [31]. Impaired mitochondria generate excessive ROS and release the proapoptotic proteins including cytochrome c, subsequently leads to intrinsic apoptosis and tissue damage [32]. Here, HQD elevated PPAR-γ protein expression in STZ-induced diabetic rats, implying the regulation of mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Huangqi Decoction Ameliorates Streptozotocin-Induced Rat Diabetic Nephropathy through Antioxidant and Regulation of the TGF-β/MAPK/PPAR-γ Signaling

Han

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Huangqi Decoction (HQD) has been traditionally used to treat diabetes mellitus in China. The present study was carried out to assess the protective effect of HQD on diabetic nephropathy (DN) using the streptozotocin-induced (STZ) diabetic rats. Methods: Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) in male Wistar rats. 40 diabetic rats were divided into 5 groups: vehicle-treated (DN group), 0.45, 0.15, 0.05 g/kg HQD-treated diabetic group (HQD group) and 1 mg/kg rosiglitazone-treated diabetic group (RGZ group). 16 normal rats were randomly divided into 2 groups: vehicle-treated normal control group (NC) and 0.45 g/kg HQD-treated normal control group (NC+0.45 g/kg HQD). At the end of 8-week experiment, we measured changes of renal pathological morphology, function, antioxidant enzyme levels and the activation of TGF-β/PPAR-γ/MAPK signaling pathway. Results: After HQD treatment, renal function, including blood urea nitrogen (BUN), 24-h albuminuria and blood glucose level were improved significantly; meanwhile, impaired kidney redox balance was diminished in diabetic rats. The activation of TGF-β, phospho-JNK, phospho-p44/42, p47 and p42 phox was blocked and the decrease in PPAR-γ in diabetic rats was attenuated by treatment with HQD in a dose-dependent manner. Conclusion: These results suggest that HQD shows therapeutic efficacy in DN characterized by renal dysfunction and pathological changes through hypoglycemic and antioxidant effects.

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Impact of high glucose and transforming growth factor–β on bioenergetic profiles in podocytes

Cited by 70 publications

References 40 publications

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Danshen injection ameliorates STZ-induced diabetic nephropathy in association with suppression of oxidative stress, pro-inflammatory factors and fibrosis

Huangqi Decoction Ameliorates Streptozotocin-Induced Rat Diabetic Nephropathy through Antioxidant and Regulation of the TGF-β/MAPK/PPAR-γ Signaling

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