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Am J Physiol Renal Physiol (April 30, 2008). doi:10.1152/ajprenal.00091.2008
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Submitted on February 21, 2008
Accepted on April 26, 2008

Silencing megalin and cubilin genes inhibits myeloma light chain endocytosis and ameliorates toxicity in human renal proximal tubule epithelial cells

Min Li1*, Saravanan Balamuthusamy1, Eric E. Simon2, and Vecihi Batuman1

1 Medicine/Nephrology, Tulane Univ. Sch. of Med., New Orleans, Louisiana, United States
2 Medicine/Nephrology, Tulane Univ. Sch. of Med., New Orleans, Louisiana, United States; Department of Internal MedicineSection of Nephrology SL45, Tulane University School of Medicine, New Orleans, Louisiana, United States

* To whom correspondence should be addressed. E-mail: minlee{at}tulane.edu.

Using target specific short interfering (si) RNAs, we silenced the tandem endocytic receptors megalin and cubilin genes in cultured human renal proximal tubule epithelial cells. Transfection by siRNA resulted in up to 90% suppression of both megalin and cubilin protein and mRNA expression. In HK-2 cells exposed to {kappa}-light chain for up to 24 h, light chain endocytosis was reduced in either megalin or cubilin silenced cells markedly, but incompletely. Simultaneous silencing of both the cubilin and megalin genes, however, resulted in near complete inhibition of light chain endocytosis, as determined by measuring {kappa}-light chain protein concentration in cell cytoplasm and by flow cytometry using FITC labeled {kappa}-light chain. In these cells, light chain induced cytokine responses (interleukin-6 and monocyte chemoattractant protein-1) and epithelial-to-mesenchymal transition as well as the associated cellular and morphological alterations were also markedly suppressed. The results demonstrate that light chain endocytosis is predominantly mediated by the megalin-cubilin tandem endocytic receptor, and identify endocytosis as a key step in light chain cytotoxicity. Blocking light chain endocytosis prevents its nephrotoxic effects on human kidney proximal tubule cells.




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