Deiodinase-3 is a thyrostat to regulate podocyte homeostasis.

Area of Science:

• Endocrinology
• Nephrology
• Molecular Biology

Background:

• Nephrotic syndrome (NS) involves kidney podocyte injury and is linked to thyroid autoimmunity.
• Thyroid hormone (TH) regulation in podocytes is not well understood.
• Type 3 deiodinase (D3) inactivates TH and its role in kidney disease is unclear.

Purpose of the Study:

• Investigate how podocytes handle thyroid hormone (TH).
• Determine the role of type 3 deiodinase (D3) in podocyte function and kidney disease.
• Explore the link between thyroid autoimmunity and NS.

Main Methods:

• Utilized immunofluorescence, qPCR, and D3 knockout mice to study D3 in healthy and injured podocytes.
• Employed surface plasmon resonance (SPR), co-immunoprecipitation, and Proximity Ligation Assay (PLA) for interaction studies.
• Assessed podocyte injury markers like foot process effacement and proteinuria.

Main Results:

• Healthy podocytes predominantly express D3, which is reduced upon injury.
• D3 mislocalization from the cell membrane to the Golgi and nucleus occurs during podocyte injury.
• D3 depletion or T3 treatment caused podocyte injury, including foot process effacement and proteinuria.
• Thyroid stimulating hormone receptor (TSH-R) activation on podocytes also led to injury.

Conclusions:

• D3 acts as a renoprotective 'thyrostat' in podocytes by minimizing T3-induced integrin activation.
• Reduced D3 function in podocytes contributes to kidney injury.
• TSH-R activation by antibodies, seen in Graves' disease, provides a mechanistic link between thyroid disorders and NS.