Renal inter-α-trypsin inhibitor heavy chain 3 increases in calcium oxalate stone-forming patients

Inter-α-trypsin inhibitor heavy-chain proteins bind to the protease inhibitor bikunin and to hyaluronan, stabilizes extracellular matrix in various tissues, and also inhibits calcium oxalate crystallization in vitro. In both normal and stone-forming patients, we found heavy chain 3 and hyaluronan in the interstitial matrix of the kidney. Osteopontin was found in the collecting duct, thin loop of Henle, and urothelial cells. In stone formers, heavy chain 3 was also present in collecting duct, thin loop, and interstitial cells. Heavy chain 3 and osteopontin colocalized in plaque matrix and urothelial cells. Within individual plaque spherules, heavy chain 3 was found in the matrix layer while osteopontin was located along the crystal–matrix interface. Bikunin was present only in the collecting duct apical membranes and the loop cell cytoplasm of stone formers colocalizing with osteopontin and heavy chain 3. Widespread heavy chain 3 was only present in stone formers, whereas osteopontin was similarly expressed in normal and stone-forming subjects except for its localization in plaques of the stone formers. This is consistent with studies linking inter-α-trypsin inhibitor components to human stone disease, although their role is still unclear. Heavy chain 3 may also play a role in stabilizing hyaluronan in the renal interstitial matrix.