Role of Tamm-Horsfall protein and uromodulin in calcium oxalate crystallization

Abstract

One of the defenses against nephrolithiasis is provided by macromolecules that modulate the nucleation, growth, aggregation and retention of crystals in the kidneys. The aim of the present study was to determine the behavior of two of these proteins, Tamm-Horsfall and uromodulin, in calcium oxalate crystallization in vitro. We studied a group of 10 male stone formers who had formed at least one kidney stone composed of calcium oxalate. They were classified as having idiopathic nephrolithiasis and had no well-known metabolic risk factors involved in kidney stone pathogenesis. Ten normal men were used as controls, as was a group consisting of five normal women and another consisting of five pregnant women. Crystallization was induced by a fixed supersaturation of calcium oxalate and measured with a Coulter Counter. All findings were confirmed by light and scanning electron microscopy. The number of particulate material deposited from patients with Tamm-Horsfall protein was higher than that of the controls (P<0.001). However, Tamm-Horsfall protein decreased the particle diameter of the stone formers when analyzed by the mode of the volume distribution curve (P<0.002) (5.64 ± 0.55 µm compared to 11.41 ± 0.48 µm of uromodulin; 15.94 ± 3.93 µm and 12.45 ± 0.97 µm of normal men Tamm-Horsfall protein and uromodulin, respectively; 8.17 ± 1.57 µm and 9.82 ± 0.95 µm of normal women Tamm-Horsfall protein and uromodulin, respectively; 12.17 ± 1.41 µm and 12.99 ± 0.51 µm of pregnant Tamm-Horsfall protein and uromodulin, respectively). Uromodulin produced fewer particles than Tamm-Horsfall protein in all groups. Nonetheless, the total volume of the crystals produced by uromodulin was higher than that produced by Tamm-Horsfall protein. Our results indicate a different effect of Tamm-Horsfall protein and uromodulin. This dual behavior suggests different functions. Tamm-Horsfall protein may act on nucleation and inhibit crystal aggregation, while uromodulin may promote aggregation of calcium oxalate crystals.

Tamm-Horsfall Glycoprotein Interacts with Renal Outer Medullary Potassium Channel ROMK2 and Regulates Its Function

“…THGP-deficient mice were shown to be severely hampered in combating colonization of bladder tissue when infected with type 1 fimbriated E. coli (8,9). Moreover, THGP by reducing calcium oxalate precipitation plays a protective role with respect to renal stone formation as demonstrated by recent studies on THGP-deficient mice prone to nephrolithiasis (10,11).…”

2D map of proteins from human renal stone matrix and evaluation of their effect on oxalate induced renal tubular epithelial cell injury

“…Under normal conditions, the crystals of calcium oxalate that form are small and well protected from crystal growth and crystal aggregation by a cover of inhibitory macromolecules. If inhibitors of crystal formation were not able to act and control their size, the final result will be nephrolithiasis (24,25). Proteins which cover crystal surface and may lead to inhibition of its growth or ability to aggregate while the same proteins bound to a surface may act to accumulate salt ions and forms a template for the first nucleus.…”

Changes in calcium oxalate crystal morphology as a function of supersaturation

“…The urine blocked formation of crystals until CaOx SS reached 10. This effect is probably due to several non-dialyzable macromolecular inhibitors present in it, like nephrocalcin, glycosaminoglycans, Tamm-Horsfall/uromodulin, and osteopontin for example (2)(3)(11)(12). When the relative SS varied between 10 and 30, there was an interesting relationship among these inhibitors of crystallization and the physicochemical burden imposed by high concentration of calcium and oxalate.…”

“…Supersaturation (SS) in relation calcium oxalate and phosphate salts is the driving force for crystallization in solutions like urine, which means that it will contain crystals that are formed spontaneously. If inhibitors of crystal formation were not able to act and control their size, the final result will be nephrolithiasis and/or nephrocalcinosis (2,3).…”