Cellular Mechanisms of Protein Metabolism in the Nephron

Abstract

The earlier studies of this series (1-6) have examined the cellular mechanisms concerned when proteins, injected into a normal experimental animal, the rat, are reabsorbed by the cells of the proximal convolution. A recent opportunity to observe "hyaline droplet" formation in human renal disease, epidemic hemorrhagic fever (EHF), in which certain therapeutic measures, i.e. the intravenous infusion of large amounts of human plasma protein, simulated the procedure of our previous experiments may serve to bridge the analogical gap between experimental and clinical observation. Moreover, since the human kidneys were the seat of extensive renal lesions, a condition which did not obtain in the normal animals of our earlier studies, an examination has been made by the experimental procedures previously used of the anomalies thus introduced into the processes of reabsorption and disposal of protein by the renal cells. The findings of these experiments have then been applied to the analysis of "hyaline droplet" formation in other examples of renal disease and a general theory of the phenomenon stated. Kinds of DropletsBefore considering droplet formation in the complex situations of human renal disease a distinction must be clearly made between the droplets of varying provenance, differing chemical constitution, and varied functional significance that may be found in the renal cells.

The Renal Lesion Associated With Hemoglobinemia

“…The present data suggest that the cellular damage is secondary to ischemia and raise the possibility that entrance of filtered protein is secondary to a resultant increase in permeability at the luminal membrane. In favor of this latter view is evidence that protein is not absorbed by the intact cells of the thick ascending limb (11), suggesting that such macromolecules gain access to the intracellular compartment only after cellular injury has occurred. It has been considered that cast formation in the ascending limb may in fact be induced by ischemic cellular injury.…”

Hazard evaluation of chemicals that cause accumulation of alpha 2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats.

“…The kidney injury seen with these neoplastic diseases has been described as similar to that produced by administration ofdecalin to male rats (46), including protein droplet accumulation in renal tubules (44,47,48). Patients with epidemic hemorrhagic fever, infused with large amounts ofconcentrated human serum albumin as a therapeutic procedure for shock, have also developed a comparable form of hyaline droplet accumulation (47 (49). Consequently, the lysosomal protease activity in male proximal tubules is lower than that offemales (49,50), implying that the male rat could be intrinsically more prone to protein overload in the renal tubules than the female rat.…”

“…In human cases of mononuclear cell leukemia, lysozyme is produced (45). The kidney injury seen with these neoplastic diseases has been described as similar to that produced by administration ofdecalin to male rats (46), including protein droplet accumulation in renal tubules (44,47,48). Patients with epidemic hemorrhagic fever, infused with large amounts ofconcentrated human serum albumin as a therapeutic procedure for shock, have also developed a comparable form of hyaline droplet accumulation (47).…”

THE EFFECT OF pH ON THE FILTRATION, REABSORPTION, AND EXCRETION OF PROTEIN BY THE RAT KIDNEY*

“…It is known that protein undergoing reabsorption in the proximal portion of the mammalian nephron can appear within the proximal convoluted tubule (PCT) cells in the form of droplets (6). Various methods have been employed for their demonstration, and of these the one using T-1824 2 (Evans blue dye) as a serum protein label (10) After this the animals were sacrificed by exsanguination from the abdominal aorta, the kidneys removed, and frozen sections from these organs prepared and examined under the ordinary light microscope.…”

“…In addition, the use of a laboratory animal afforded ready access to renal tissue in which the formation of "protein absorption droplets" (6) within the cells of the proximal convoluted tubules could be studied histologically.…”