Proteinuria and phenotypic change of proximal tubular cells.

Abstract

Terminal renal failure is the final common fate of chronic nephropathies independent of the type of initial insult. The outstanding review by Brenner et al. (1) in 1982 introduced the idea that glomerular hemodynamic changes that develop as compensatory adaptation to irreversible nephron damage cause progressive deterioration of function and structure of the remaining nephrons. After reduction of renal mass in rats, remnant intact nephrons undergo sudden hypertrophy with concomitant lowering of arteriolar resistance and increased glomerular plasma flow that results from a differential decrease in vessel tone that is less in afferent than efferent arterioles. This fosters adaptive increase in glomerular capillary hydraulic pressure and more filtrate per nephron, changes, however, that are detrimental in the long term. The increase in intraglomerular capillary pressure alters the size-selective function of the glomerular barrier and causes protein ultrafiltration. Abnormally filtered proteins have an intrinsic renal toxicity linked to their over-reabsorption by proximal tubular cells and activation of tubular-dependent pathways of interstitial inflammation and fibrosis (2,3). The functional importance of tubulointerstitial events in progressive renal disease is supported by evidence that the severity of tubular interstitial damage strongly correlates with the risk of renal failure, even better than do the glomerular lesions. The relationship between proteinuria and tubulointerstitial damage was suggested by early studies in renal biopsies of rats with age-related proteinuria (4) and adriamycin nephrosis (5), showing that protein reabsorption droplets accumulate in the cytoplasm of proximal tubular cells with focal breaks of the tubular basement membrane and extravasation of the tubular content into the renal interstitium, followed by an inflammatory reaction and tubulointerstitial lesions. Furthermore, in models of overload proteinuria, repeated injections of albumin in the rat increased glomerular barrier permeability and caused massive proteinuria (6,7) and tubular changes with heavy macrophage and T-lymphocyte infiltration into the renal interstitium (8). That excess protein reabsorption by proximal tubular cells may play a role in the development of interstitial inflammation has been documented by a recent study of our group in two different models of proteinuric nephropathies (9). In rats with 5/6 nephrectomy, albumin and IgG accumulation in proximal tubular cells was visualized in the early stage, preceding the interstitial infiltration of major histocompatability complex II–positive cells and macrophages. The infiltrating cells concentrated almost exclusively in regions containing IgG-positive proximal tubules and tubules with luminal casts. Similar patterns were found in the immune model of passive Heymann nephritis indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Protein Traffic as a Fosterer of Tubular Cell Dysfunction Filtered albumin and other proteins that accumulate within intracellular compartments of proximal tubular cells perturb cell function by several mechanisms. Studies have contributed to define the biochemical pathways specifically activated by excessive tubular reabsorption, and evidence is now available that protein overloading of proximal tubular cells in culture activates the transcription of a number of genes encoding for vasoactive, inflammatory, and fibrogenic molecules with potential toxic effects on the kidney.