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Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease

Sanja Sever1, Mehmet M Altintas, Sharif R Nankoe

  • 1Department of Medicine, Nephrology Division and Program in Glomerular Disease, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts 02129, USA. ssever@partners.org

The Journal of Clinical Investigation
|August 3, 2007
PubMed

Insights

Dynamin is crucial for kidney podocyte function. Proteolytic cleavage of dynamin causes proteinuric kidney disease, but resistant dynamin mutants can restore podocyte function and resolve proteinuria.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Medicine

Background:

  • Kidney podocytes and their foot processes are vital for the ultrafiltration barrier, preventing protein loss in urine (proteinuria).
  • The GTPase dynamin plays a critical role in maintaining podocyte structure and function.

Purpose of the Study:

  • To investigate the role of dynamin in podocyte function and its involvement in proteinuric kidney disease.
  • To identify mechanisms by which dynamin is regulated under pathological conditions.

Main Methods:

  • Utilized molecular biology techniques to study dynamin cleavage by cathepsin L.
  • Developed and tested dynamin mutants resistant to cathepsin L cleavage in mouse models of kidney disease.

Main Results:

  • Cytoplasmic cathepsin L cleaves dynamin at a conserved site during proteinuric kidney disease, leading to actin cytoskeleton reorganization and proteinuria.
  • Dynamin mutants lacking or shielding the cathepsin L cleavage site demonstrated resistance to cleavage.
  • Delivery of these resistant mutants in mice restored podocyte function and resolved proteinuria.

Conclusions:

  • Dynamin is an essential regulator of renal permselectivity.
  • Specific proteolysis of dynamin by cathepsin L is a key mechanism driving proteinuria in kidney disease.
  • Therapeutic strategies targeting dynamin cleavage offer potential for treating proteinuric kidney disorders.

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