Effects of andrographolide on renal tubulointersticial injury and fibrosis. Evidence of its mechanism of action |
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| Affiliation: | 1. Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China;2. The Department of Endocrinology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China;3. Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510632, China;1. Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China;2. State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Third Military Medical University, Chongqing 400038, China;1. Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;2. Department of Microbiology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;3. Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA |
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| Abstract: | BackgroundDiabetic nephropathy (DN) is associated with renal interstitial injury and fibrosis. Our previous study showed that andrographolide protected against the progression of DN and high glucose (HG)-induced mesangial dysfunction. However, the protective effects of andrographolide on renal tubular epithelial cells have not been fully elucidated.PurposeTo determine the protective effects of andrographolide on renal tubular damage and explore the underlying mechanism.Study designHuman tubular epithelial cells (HK-2 cells) were treated with andrographolide (5 and 10 μM) under HG conditions. Diabetic mice were treated with andrographolide (i.p. 2 and 4 mg/kg, twice per week).MethodsWestern blotting, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence and flow cytometry were used to analyze the effects of andrographolide on renal tubular injury and fibrotic mechanisms in HK-2 cells. The protective effects of andrographolide against renal tubulointerstitial injury and fibrosis were investigated in diabetic mice fed a high-fat diet (HFD). Renal interstitial tissue was collected at sacrifice for immunohistochemistry, immunofluorescence analysis, RT-PCR and Western blotting to analyze the effects of andrographolide on renal tubular injury and fibrosis.ResultsIn vitro assay results indicated that andrographolide (5 and 10 μM) effectively inhibited HG-induced apoptosis, epithelial-mesenchymal transition (EMT) and collagen deposition in HK-2 cells. Mechanistically, HG stimulated mitochondrial reactive oxygen species (mtROS)-mediated NOD-like receptor family and pyrin domain-containing protein 3 (NLRP3) inflammasome activation and EMT in tubular epithelial cells, and andrographolide (5 and 10 μM) inhibited these effects by ameliorating mitochondrial dysfunction. In vivo, treatment with andrographolide (2 and 4 mg/kg) inhibited renal tubular cell apoptosis, EMT and tubulointerstitial fibrosis, mitochondrial dysfunction and NLRP3 inflammasome activation in diabetic mice.ConclusionAndrographolide (5 and 10 μM) prevents HG-induced renal tubular cell damage, and andrographolide (2 and 4 mg/kg) protects against the progression of diabetic tubular injury and fibrosis in mice by suppressing mitochondrial dysfunction and NLRP3 inflammasome activation. |
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