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

Han, Huiying; A, Cao; Wang, Li; Guo, Hengjiang; Zang, Yingjun; Li, Zezheng; Zhang, Xuemei; Peng, Wen

doi:10.1159/000479834

Cited by 47 publications

(41 citation statements)

References 39 publications

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“…MAPK-JNK activation augments podocyte apoptosis in diabetic nephropathy mice [16]. In contrast, inhibition of JNK phosphorylation improves renal function in diabetic rats [17]. Notably, a subgroup of enzymes within the PTP superfamily, termed dual specificity phosphatases, are recently identified as upstream inhibitors of the MAPK pathway, which are now named the MAPK Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry phosphatases (MKPs) [18].…”

Section: Introductionmentioning

confidence: 99%

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Zhang¹,

Feng²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.

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Section: Introductionmentioning

confidence: 99%

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Zhang¹,

Feng²,

Wang³

et al. 2018

Cell Physiol Biochem

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“…MAPK, a serine/threonine protein kinase, is found throughout various cells and consists of three major subtype groups: extracellular signal-regulated kinases (ERK); c-Jun amino-terminal kinases (JNK); and p38 MAPK (p38) [10, 11]. Once cells are stimulated with a drug or cytokines, MAPKs are activated and assist with differentiation, apoptosis, energy metabolism, or the stress response by regulating their downstream signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

Expressions and Regulatory Effects of P38/ERK/JNK Mapks in the Adipogenic Trans-Differentiation of C2C12 Myoblasts

Qi¹,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Myoblasts and muscle satellite cells have the potential to transdifferentiate into adipocytes or adipocyte-like cells. Previous studies suggest that mitogen-activated protein kinase (MAPK) is critical to adipogenic trans-differentiation of muscle cells. ERK1/2, P38 and JNK are three major MAPK family members; their activation and regulatory functions during adipogenic trans-differentiation of myoblasts are investigated. Methods: C2C12 myoblasts were cultured and induced for adipogenic trans-differentiation. Activation patterns of MAPKs were assayed using protein microarray and Western blot. Three specific MAPK blockers, U0126, SB20358 and SP600125, were used to block ERK1/2, P38 and JNK during trans-differentiation. Cellular adipogenesis was measured using staining and morphological observations of cells and expression changes in adipogenic genes. Results: Inhibitors reduced phosphorylation of corresponding MAPK and produced unique cellular effects. Suppressing P38 promoted adipogenic trans-differentiation and intensified adipolytic metabolism in differentiated cells. However, inhibition of ERK1/2 had the opposite effects on adipogenesis and no effect on adipolysis. Blocking JNK weakly blocked trans-differentiation but stimulated adipolysis and induced apoptosis. Conclusion: Three MAPKs participate in the regulation of myoblast adipogenic trans-differentiation by controlling adipogenic and adipolysis metabolism.

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“…The presence of antioxidant according to Jha et al (2016) can ROS into nonreactive oxygen molecules which is harmless to cells (Jha et al, 2016). Also, it obstructs glucose absorption through inhibition of carbohydrate-hydrolyzing enzymes such as αglucosidase and α-amylase and down-regulates the TGF-β expression and FN level by decreasing NADPH oxidase expression (Widowati et al, 2018;Manaharan et al, 2012;Han et al, 2017;Prahastuti et al, 2019a). Table IV shows that EEDS is capable to lower ROS level mesangial cells treated with 5 and 10 mM glucose compared to the positive control.…”

Section: Resultsmentioning

confidence: 99%

Ethanol Extract of Detam 1 Soybean Seed (Glycine Max L. Merr) for Chronic Kidney Disease Therapy by In Vitro Study

et al. 2019

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Chronic Kidney Disease (CKD) has increased incidence and prevalence in developing nations. In this in vitro study, we evaluated the cells proliferative effects, fibronectin (FN), transforming growth factor β (TGF-β1), and Reactive oxygen species (ROS) - level inhibition potential of ethanol extract of detam 1 soybean seed (EEDS) on glucose-induced kidney mesangial cells (SV40 MES 13). The cells proliferation assay used 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)2H-tetrazolium (MTS) assay. FN and TGF-β1 level were measured using ELISA assay kit and ROS level using flow cytometry. Level of FN, TGF-β1 and ROS, on CKD cells model (5 mM, 10 mM glucose-induced mesangial cell) treated with EEDS 6.25 µg/mL were lower significantly compared to positive control, EEDS improve cells viability and decrease FN, TGF-β1 and ROS level in glucose-induced kidney mesangial cells as CKD cells model.

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

Cited by 47 publications

References 39 publications

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Expressions and Regulatory Effects of P38/ERK/JNK Mapks in the Adipogenic Trans-Differentiation of C2C12 Myoblasts

Ethanol Extract of Detam 1 Soybean Seed (Glycine Max L. Merr) for Chronic Kidney Disease Therapy by In Vitro Study

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