Tyro3 is a podocyte protective factor in glomerular disease.

Area of Science:

• Nephrology
• Molecular Biology
• Immunology

Background:

• Protein S has a protective role in early diabetic kidney disease (DKD).
• Protein S activates TYRO3, AXL, and MER (TAM) receptors, mediating anti-inflammatory and antiapoptotic effects.
• Previous studies indicated TYRO3 as the primary mediator of protein S's effects in diabetic kidneys.

Purpose of the Study:

• To investigate the role of TYRO3 in glomerular diseases, particularly diabetic kidney disease.
• To elucidate the expression patterns and functional significance of TYRO3 in podocytes.
• To explore the therapeutic potential of targeting TYRO3 in kidney diseases.

Main Methods:

• Analysis of TYRO3 mRNA and protein expression in human glomeruli and podocytes.
• Functional studies using zebrafish larvae with morpholino-mediated knockdown of tyro3.
• Genetic ablation and overexpression studies in murine models of DKD, Adriamycin-induced nephropathy (ADRN), and HIV-associated nephropathy (HIVAN).
• Investigation of the regulatory pathways involving TNF-α/NF-κB and AKT signaling.

Main Results:

• TYRO3 mRNA is enriched in human glomeruli and expressed in podocytes.
• Glomerular TYRO3 expression increased in mild DKD but decreased in progressive DKD and FSGS.
• TYRO3 deficiency exacerbated kidney injury and albuminuria in mouse models.
• TYRO3 overexpression in podocytes attenuated kidney injury and albuminuria across multiple nephropathy models.
• TYRO3 signaling conferred antiapoptotic effects via AKT activation in podocytes.
• TNF-α/NF-κB pathway activation suppressed TYRO3 expression.

Conclusions:

• TYRO3 plays a crucial role in maintaining podocyte function and protecting against glomerular injury.
• Decreased TYRO3 expression, potentially due to TNF-α/NF-κB activation, contributes to progressive DKD and FSGS.
• TYRO3 represents a promising therapeutic target for glomerular diseases.