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Clinical nephrologists have long recognized the associAfter binding, albumin reabsorption occurs by endocytosis into an intracellular vesicular trafficking system, ation between heavy proteinuria and the tendency for progression of renal failure. Progressive renal impairwith delivery of the majority of the reabsorbed albumin ment is characterized by progressive interstitial scarring to a lysosomal compartment. Here it is degraded to its and tubular atrophy, and proteinuria is strongly impliccomponent amino acids which are then returned to the ated in the pathogenesis of this tubulo-interstitial circulation rather than being excreted in the urine. The lesion. Proximal tubular cells are exposed to filtered endocytic process itself is subject to complex regulation protein, most notably albumin, in health, but are by heterotrimeric GTP-binding proteins, and the exposed to much higher concentrations in diseases of enzyme phosphatidylinositol 3-kinase (PI 3-kinase) reduced glomerular permselectivity. Traditional [4,5]. dogma, however, suggests that albumin is a benign Albumin is not simply an inert piece of cargo molecule, and the mechanisms by which it may induce reabsorbed and degraded by the proximal tubular adverse pathophysiological events in the kidney have epithelium. Indeed, a growing body of evidence also not been clear. Thus the mechanism of interaction of implicates albumin as an important regulator of funcalbumin with the proximal tubule is of considerable tion and dysfunction in a number of other cell types. interest to nephrologists. In endothelial cells, albumin modulates vascular perFiltered albumin is reabsorbed by the proximal meability possibly via inducing changes in intracellular tubular epithelium, and these cells are often heavily calcium [6 ]. Albumin binding to endothelial cells not vacuolated in nephrotic patients. The vacuoles contain only precedes its endocytosis, but also initiates an predominantly protein reabsorbed from the proximal intracellular tyrosine kinase cascade with phosphoryltubular fluid, but lipid accumulation is also observed. ation of multiple substrates [7]. Survival of endothelial Cellular architecture is disturbed markedly by this cells in serum-free conditions is greatly enhanced by vacuolation, and it is likely that cells with such disoralbumin, although the mechanism of this effect is dered architecture also have disordered function. unknown [8]. Some authors have postulated an importAlbumin reabsorption in the proximal tubule occurs ant role for albumin in the pathogenesis of brain injury by receptor-mediated endocyotsis. Using opossum when the blood–brain barrier is breached. Again it is kidney cells as a model, albumin has been shown to thought that albumin may induce changes in intracellubind to both high-affinity low-capacity, and low-affinity lar calcium in astrocytes and glia [9]. high-capacity receptor systems [1,2]. The characterCultured proximal tubular cells proliferate in istics of the higher affinity system suggest that this response to albumin in serum-free conditions. The use receptor would be capable of mediating the reabsorpof yeast recombinant albumin eliminates the possibility tion of the albumin normally crossing the glomerular that this effect may be mediated by a serum-derived filtration barrier in health. The identity of the recepfactor bound to albumin. Upon binding to proximal tor(s) remains unresolved. Megalin has been shown tubular cells, recombinant albumin stimulates the activconvincingly to bind albumin in proximal tubular ity of a kinase cascade involving PI 3-kinase and pp70s6 segments [3], but it is possible that other lower molecukinase [10]. The proliferative effect of recombinant lar weight receptors may also participate in the albumin albumin is dependent on the activity of both these reabsorptive process. enzymes. Interestingly, activation of these enzymes by albumin is observed at concentrations likely to prevail Correspondence and offprint requests to: Dr Nigel J. Brunskill, in the proximal tubule in health, indicating that under Department of Cell Physiology and Pharmacology, University of physiological conditions albumin may play a role in Leicester, Faculty of Medicine and Biological Sciences, Medical Sciences Building, University Rd, Leicester LE1 9HN, UK. the maintenance of proximal tubular homeostasis and

Albumin handling by proximal tubular cells: mechanisms and mediators