The Akt-mTORC1 pathway mediates Axl receptor tyrosine kinase-induced mesangial cell proliferation

Area of Science:

• Nephrology
• Molecular Biology
• Cell Signaling

Background:

• Glomerulonephritis (GN) often involves mesangial cell proliferation.
• TAM family receptor tyrosine kinases (Axl, Mer, Tyro-3) regulate cell survival, proliferation, and apoptotic cell clearance.
• Axl signaling contributes to GN pathogenesis by promoting mesangial cell proliferation.

Purpose of the Study:

• To investigate the downstream signaling pathways activated by Axl in renal mesangial cells.
• To determine Axl's role in mesangial cell phagocytosis of apoptotic cells.
• To explore the therapeutic potential of targeting Axl in GN.

Main Methods:

• Stimulation of renal mesangial cells with Axl agonists.
• Measurement of intracellular calcium (Ca2+).
• Analysis of NF-κB, mTOR, mTORC1, Akt, and ribosomal protein S6 activation.
• Assessment of apoptotic cell phagocytosis by mesangial cells and peritoneal macrophages.

Main Results:

• Axl stimulation increased intracellular Ca2+ and activated NF-κB, mTOR, mTORC1, and Akt signaling pathways.
• Axl-induced Akt activation was upstream of NF-κB and mTOR activation.
• NF-κB activation by Axl led to Bcl-xl up-regulation.
• Axl played a more significant role than Mer in mesangial cell apoptotic cell phagocytosis.

Conclusions:

• Axl signaling in mesangial cells activates key pro-proliferative and survival pathways (NF-κB, mTORC1).
• Axl may mediate mesangial cell phagocytosis of apoptotic cells.
• Targeting Axl presents a potential therapeutic strategy for glomerulonephritis.