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Paeoniflorin ameliorates AGEs-induced mesangial cell injury through inhibiting RAGE/mTOR/autophagy pathway
Juan Chen1, Di Zhao2, Maomao Zhu1
1Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, Nanjing, 210028, PR China.
Abstract:
Glomerular mesangial cell plays a vital role in diabetic nephropathy (DN). Recent research has demonstrated that autophagy involved in the development of DN. Paeoniflorin (PF), a monoterpene glucoside, has been proved to attenuate advanced glycation end products (AGEs)-induced mesangial cell injury. However, the regulatory mechanism of PF on autophagy in mesangial cell remains unclear. The aim of this study was to explore the effect of PF on autophagy in AGEs-induced mesangial cell dysfunction. In this study, the leakage of the lactic dehydrogenase (LDH) into the extracellular medium was measured by LDH kit. Transmission electron microscopy (TEM) and mRFP-GFP-microtubule-associated protein light chain 3 (LC3) transfection were performed to observe the formation of autophagy in AGEs-induced mesangial cell. The RAGE/mTOR/autophagy pathway was analyzed by western blotting and small-interfering RNA transfection. Our results showed that the expression of LC3II, p62 were changed in a time-dependent manner in AGEs-stimulated mesangial cell. While PF could decrease the expression of LC3II/LC3I and reduce the number of autophagosomes. Knockdown of Atg5 promoted the protective effect of PF on AGEs-induced HBZY-1 injury. Furthermore, we found PF inhibited autophagy at least partly through inhibiting RAGE and upregulating the level of p-mTOR to against AGEs-induced mesangial cell dysfunction. Thus, PF could be a potential agent for the treatment of DN.
Insights
Paeoniflorin (PF) may treat diabetic nephropathy by inhibiting autophagy in mesangial cells. This study found PF reduces autophagosomes and protects against advanced glycation end product (AGE) injury by affecting the RAGE/mTOR pathway.
Area of Science:
- Cell Biology
- Pharmacology
- Nephrology
Background:
- Diabetic nephropathy (DN) involves glomerular mesangial cells and autophagy.
- Advanced glycation end products (AGEs) induce mesangial cell injury.
- Paeoniflorin (PF) shows potential in attenuating AGE-induced damage, but its mechanism on autophagy is unknown.
Purpose of the Study:
- To investigate the effect of PF on autophagy in AGE-induced mesangial cell dysfunction.
- To elucidate the regulatory mechanism of PF on autophagy in the context of DN.
Main Methods:
- Assessed lactate dehydrogenase (LDH) leakage.
- Utilized transmission electron microscopy (TEM) and mRFP-GFP-LC3 transfection to observe autophagy.
- Analyzed the RAGE/mTOR/autophagy pathway via western blotting and small-interfering RNA (siRNA).
Main Results:
- AGEs altered the expression of LC3II and p62 in mesangial cells.
- PF decreased LC3II/LC3I expression and reduced autophagosome formation.
- Knockdown of Atg5 enhanced PF's protective effects.
- PF inhibited autophagy by suppressing RAGE and upregulating p-mTOR.
Conclusions:
- Paeoniflorin inhibits autophagy, at least partially, by modulating the RAGE/mTOR pathway.
- PF demonstrates protective effects against AGE-induced mesangial cell dysfunction.
- PF is a potential therapeutic agent for diabetic nephropathy.
