Aminophylline suppresses chronic renal failure progression by activating SIRT1/AMPK/mTOR-dependent autophagy

Area of Science:

• Nephrology
• Pharmacology
• Cell Biology

Background:

• Chronic renal failure (CRF) is a progressive urinary system disease lacking effective treatments.
• Investigating novel therapeutic strategies for CRF is crucial to mitigate disease progression and renal damage.

Purpose of the Study:

• To explore the protective effects and underlying mechanisms of aminophylline in preventing chronic renal failure (CRF) development.
• To elucidate aminophylline's impact on renal function, histological integrity, apoptosis, and key molecular pathways in a rat model.

Main Methods:

• Establishment of a 5/6 nephrectomy rat model to simulate chronic renal failure (CRF).
• Quantification of serum creatinine (SCR), urinary protein (UPR), and blood urea nitrogen (BUN) levels.
• Histological examination of renal tissues using H&E, Masson, and PAS staining.
• Western blot and immunofluorescence analysis for protein expression (nephrin, podocin, SIRT1, AMPK, mTOR, LC3B).
• TUNEL assay to assess glomerular cell apoptosis.

Main Results:

• Aminophylline significantly reduced SCR, UPR, and BUN levels, alleviating renal tissue injury in CRF rats.
• Aminophylline treatment increased protein expression of nephrin, podocin, SIRT1, p-AMPK, and p-ULK1, while decreasing p-mTOR.
• Aminophylline enhanced autophagy marker LC3B and reduced glomerular apoptosis in CRF rats.
• Modulation of SIRT1/AMPK/mTOR pathway and autophagy was confirmed through experiments with resveratrol, selisistat, RAPA, and 3-MA.

Conclusions:

• Aminophylline demonstrates significant renoprotective effects in a rat model of chronic renal failure (CRF).
• The therapeutic action of aminophylline involves the modulation of the SIRT1/AMPK/mTOR signaling pathway, promoting autophagy and reducing apoptosis.
• Aminophylline represents a promising therapeutic agent for suppressing chronic renal failure progression.