Oleanolic acid and<i>N</i>-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model

Lee, Eun Soo; Kim, Hong Min; Kang, Jin Ku; Lee, Eun Young; Yadav, Dhananjay; Kwon, Mi Hye; Kim, You Mi; Kim, Hyeon Soo; Chung, Choon Hee

doi:10.1093/ndt/gfv377

Cited by 84 publications

(62 citation statements)

References 34 publications

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“…Both increased ROS production and ER stress were observed in the current study, with similar results with other independent groups [28, 29]. In this study, we set to explore the molecular mechanisms underlying ROS/ER stressduring DN progression.…”

Section: Discussionsupporting

confidence: 89%

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Zhao

Zhong

et al. 2017

Oncotarget

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Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients. Endoplasmic reticulum (ER) stress caused by reactive oxygen species (ROS) is associated with DN progression. Epidermal growth factor receptor (EGFR) mediates oxidative stress and damage of cardiomyocytes in diabetic mice. Here we demonstrated that AG1478, a specific inhibitor of EGFR, blocked EGFR and AKT phosphorylation in diabetic mice. Oxidative stress and ER stress markers were eliminated after AG1478 administration. AG1478 decreased pro-fibrotic genes TGF-β and collagen IV. Furthermore, we found that high glucose (HG) induced oxidative stress and ER stress, and subsequently increased ATF4 and CHOP. These changes were eliminated by either AG1478 or ROS scavenger N-acetyl-L-cysteine (NAC) administration. These results were confirmed by knock-down approaches in renal mesangial SV40 cells. However, AG1478, not NAC, reversed HG induced EGFR and AKT phosphorylation. These results suggest that EGFR/AKT/ROS/ER stress signaling plays an essential role in DN development and inhibiting EGFR may serve as a potential therapeutic strategy in diabetic kidney diseases.

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Section: Discussionsupporting

confidence: 89%

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Zhao

Zhong

et al. 2017

Oncotarget

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“…Poricoic acid G and poricoic acid H suppressed TGF-β/Smad pathway by selectively inhibiting the phosphorylation of Smad3 via blocking the interactions of SARA with TGFβRI and Smad3 [178]. Similarly, renal fibrosis in a variety of animal models were attenuated or suppressed through TGF-β/Smads and NF-κB-mediated pathways by administration of compounds isolated from various natural products, such as GQ5 [179], arctigenin [98], curcumin [180,181], resveratrol [182], berberine [183,184], sinomenine [185], rutin [186], oxymatrine [149,187], bergenin [188], oleanolic acid [189], tanshinone IIA [190], leonurine [191]; (+/−)-sinensilactam A [192], epigallocatechin-3-gallate [193] and astragaloside IV [194,195].…”

Section: Specific Inhibition Of Smads Signaling By Natural Productsmentioning

confidence: 99%

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Chen

Yang

et al. 2018

Biomedicine & Pharmacotherapy

268

200

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Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-β1 (TGF-β1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF-β1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-β1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-β1. The Smad signaling system plays a central role in regulation of TGF-β1 and TGF-β/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-β/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF-β1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-β-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF-κB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-κB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-β1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD.

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“…In the context of renal fibrosis, [57]. Similarly, renal fibrosis in a variety of animal models were mitigated via TGF-β/Smad pathways by administration of natural products, such as GQ5 [58], curcumin [59,60], arctigenin [61], resveratrol [62], sinomenine [63], berberine [64,65], leonurine [66], rutin [67], bergenin [68], oxymatrine [69,70], oleanolic acid [71], tanshinone IIA [72], astragaloside IV [73,74], (+/-)sinensilactam A [75] and epigallocatechin-3-gallate [76]. Besides, inflammation could in the activation of immune cells, including macrophages, dendritic cells and T cells.…”

Section: Tgf-β/smad In Renal Fibrosismentioning

confidence: 99%

Action Mechanisms and Therapeutic Targets of Renal Fibrosis

Shang

Zhang

et al. 2018

JNA

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Renal fibrosis was a chronic and progressive process affecting kidneys in chronic kidney disease (CKD), regardless of cause. Although no effective targeted therapy yet existed to retard renal fibrosis, a number of important recent advances have highlighted the cellular and molecular mechanisms underlying the renal fibrosis. The advances including TGF-β/Smad pathway, oxidative stress and inflammation, hypoxia and gut microbiota-derived from uremic solutes were highlighted that could provide therapeutic targets. New therapeutic targets and strategies that are particularly promising for development of new treatments for patients with CKD were also highlighted.

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Oleanolic acid andN-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model

Abstract: The findings in this study suggest that OA and NAC have therapeutic effects for DN through an antioxidant effect and ER stress reduction.

Cited by 84 publications

References 34 publications

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Action Mechanisms and Therapeutic Targets of Renal Fibrosis

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