Dopamine agonist pramipexole halts leflunomide nephrotoxicity: A dual strike on TLR4-Driven inflammation and PI3K/Akt...

Area of Science:

• Pharmacology
• Nephrology
• Immunology

Background:

• Leflunomide, an immunosuppressant for autoimmune diseases, can cause kidney damage (nephrotoxicity).
• Effective treatments to prevent leflunomide-induced kidney injury are limited.
• Pramipexole, a dopamine agonist, has anti-inflammatory effects.

Purpose of the Study:

• To investigate pramipexole's potential to protect against leflunomide-induced kidney injury in mice.
• To elucidate the molecular mechanisms underlying pramipexole's nephroprotective effects.

Main Methods:

• A murine model of chronic leflunomide exposure was used.
• Renal function, oxidative stress, inflammation, and apoptosis markers were assessed.
• Key signaling pathways including TLR4/MyD88/TRAF6, PI3K/Akt, and NF-κB were analyzed.
• The role of PI3K/Akt signaling was confirmed using Wortmannin.

Main Results:

• Leflunomide induced kidney dysfunction, oxidative stress, inflammation, and apoptosis via TLR4/MyD88/TRAF6 and suppressed PI3K/Akt.
• Pramipexole treatment reversed these effects, reducing NF-κB signaling and enhancing PI3K/Akt activation.
• Pramipexole upregulated the Nrf2 antioxidant response and modulated apoptosis markers (Bax, Bcl-2, caspase-3).
• Pramipexole also decreased IL-17 and CD4+ T-cell activation, reducing renal immunopathology.

Conclusions:

• Pramipexole demonstrates significant nephroprotective potential against leflunomide-induced renal toxicity.
• The protective effects are mediated by inhibiting inflammatory pathways (NF-κB, IL-17) and activating antioxidant and survival pathways (Nrf2, PI3K/Akt).
• Pramipexole represents a potential therapeutic strategy for managing leflunomide-associated kidney injury.