Effect of osthole on advanced glycation end products-induced renal tubular hypertrophy and role of klotho in its mechanism of action
Autor: | Yu-Lin Yang, Yi-Ling Ye, Jinn-Yuh Guh, Jean-Yu Hwang, Lea-Yea Chuang, Wei-Chih Kan, Jau-Shyang Huang |
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Rok vydání: | 2019 |
Předmět: |
Glycation End Products
Advanced STAT3 Transcription Factor medicine.medical_specialty Pharmaceutical Science Suppressor of Cytokine Signaling Proteins urologic and male genital diseases Cell Line Muscle hypertrophy 03 medical and health sciences 0302 clinical medicine Antigens Neoplasm Coumarins Glycation Internal medicine Drug Discovery medicine Humans Diabetic Nephropathies SOCS3 Viability assay Klotho Proteins Klotho Glucuronidase 030304 developmental biology Pharmacology 0303 health sciences Janus kinase 2 biology Chemistry Suppressor of cytokine signaling 1 Cell Cycle Hypertrophy Janus Kinase 2 female genital diseases and pregnancy complications Kidney Tubules Endocrinology Complementary and alternative medicine 030220 oncology & carcinogenesis biology.protein Molecular Medicine Mitogen-Activated Protein Kinases Janus kinase |
Zdroj: | Phytomedicine. 53:205-212 |
ISSN: | 0944-7113 |
Popis: | Background Osthole has been widely reported to have pharmacological activities such as anti-cancer, anti-inflammation and anti-hyperlipidemic effects. Klotho was identified as an anti-senescence protein in a variety of tissues. Loss of klotho has been associated with chronic kidney disease. However, potential roles and molecular events for osthole and klotho in diabetic nephropathy remain unclear. Purpose In the current study, we undertook to study the effect of osthole on klotho expression in advanced glycation end products (AGE)-cultured human renal proximal tubular cells, and to investigate the molecular mechanisms of osthole and exogenous klotho against AGE-induced renal tubular hypertrophy. Methods Cell viability was elucidated by MTT assay. Protein expression was measured by Western blotting. mRNA level was analyzed by real-time PCR. Cellular hypertrophy growth was evaluated by hypertrophy index. Relative cell size was detected by flow cytometry. Results We found that raising the ambient AGE concentration causes a dose-dependent decrease in klotho synthesis. Osthole significantly increased AGE-inhibited klotho mRNA and protein expression. Osthole and exogenous klotho treatments significantly attenuated AGE-induced Janus kinase 2 (JAK2)-signal transducers and activators of transcription 1 (STAT1) and STAT3 activation. Moreover, protein levels of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 were augmented by osthole and exogenous klotho. The abilities of osthole and exogenous klotho to reverse AGE-induced cellular hypertrophy were verified by the observation that osthole and exogenous klotho inhibited p21Waf1/Cip1/collagen IV/RAGE expression, total protein content, and cell size. Conclusion Consequently, we found that osthole attenuated AGE-induced renal tubular hypertrophy via induction of klotho expression and suppression of the JAK2-STAT1/STAT3 signaling. These results also showed that klotho might be used as a unique molecular target for the treatment of diabetic nephropathy. |
Databáze: | OpenAIRE |
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