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From the Department of Medicine and Department of Physiology and Biophysics, Division of Nephrology, Nephrology Research and Training Center, Comprehensive Cancer Center, and Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, Alabama; and the Department of Veterans Affairs Medical Center, Birmingham, Alabama
Cast nephropathy, or myeloma kidney, is a
potentially reversible cause of chronic renal failure. In this
condition, filtered light chains bind to a common site on
Tamm-Horsfall protein (THP), which is produced by cells of the
thick ascending limb of the loop of Henle. Subsequent aggregation of
these proteins produces casts that obstruct tubule fluid flow and
results in renal failure. In the present study, we used the
yeast two-hybrid system to determine the site of interaction of light
chains with THP. The third complementarity-determining region (CDR3) of
both 
and 
light chains interacted with THP. These findings were
confirmed in a series of competition studies using a synthetic peptide
that corresponded to the CDR3 region and purified THP and light chains.
Variations in the CDR3 sequence of the light chain affected binding.
Thus, the current studies increase our understanding of the
process of cast formation and provide an opportunity to develop
strategies that may inhibit this interaction and prevent the clinical
manifestations of myeloma kidney.
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