Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury

Area of Science:

• Nephrology
• Molecular Biology
• Immunology

Background:

• Circulating tumor necrosis factor (TNF) and its receptors (TNFR1, TNFR2) are linked to diabetic kidney disease (DKD) progression.
• The specific role of local and systemic TNF in causing podocyte injury within DKD remains unclear.

Purpose of the Study:

• To investigate the function of local and systemic TNF in podocyte injury and its contribution to DKD.
• To elucidate the molecular mechanisms underlying TNF-induced podocyte damage.

Main Methods:

• Cultured human podocytes with sera from DKD and focal segmental glomerulosclerosis (FSGS) patients.
• Administered exogenous TNF and studied local TNF expression.
• Utilized mouse models with podocyte-specific ABCA1 or NFATc1 deficiency/activation.
• Assessed albuminuria, podocyte apoptosis, cholesterol efflux (ABCA1), cholesterol esterification (SOAT1), and NFATc1 activation.

Main Results:

• Local TNF, not just circulating levels, induced free cholesterol-dependent podocyte apoptosis.
• TNF impaired podocyte function by reducing ABCA1-mediated cholesterol efflux and SOAT1 esterification.
• TNF-induced albuminuria was exacerbated by podocyte-specific ABCA1 deficiency and partially prevented by cholesterol depletion.
• NFATc1 mediated TNF-induced apoptosis, and its activation was linked to ABCA1 function and cholesterol levels.

Conclusions:

• Local TNF is sufficient to cause free cholesterol-dependent podocyte injury via an NFATc1/ABCA1 pathway.
• This mechanism operates independently of circulating TNF, TNFR1, or TNFR2 serum levels.
• Findings highlight a novel therapeutic target for mitigating DKD progression by managing intra-renal TNF signaling and cholesterol homeostasis.