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
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
Externí odkaz: