Albumin Is Recycled from the Primary Urine by Tubular Transcytosis

Abstract

Under physiologic conditions, significant amounts of plasma protein pass the renal filter and are reabsorbed by proximal tubular cells, but it is not clear whether the endocytosed protein, particularly albumin, is degraded in lysosomes or returned to the circulatory system intact. To resolve this question, a transgenic mouse with podocyte-specific expression of doxycycline-inducible tagged murine albumin was developed. To assess potential glomerular backfiltration, two types of albumin with different charges were expressed. On administration of doxycycline, podocytes expressed either of the two types of transgenic albumin, which were secreted into the primary filtrate and reabsorbed by proximal tubular cells, resulting in serum accumulation. Renal transplantation experiments confirmed that extrarenal transcription of transgenic albumin was unlikely to account for these results. Genetic deletion of the neonatal Fc receptor (FcRn), which rescues albumin and IgG from lysosomal degradation, abolished transcytosis of both types of transgenic albumin and IgG in proximal tubular cells. In summary, we provide evidence of a transcytosis within the kidney tubular system that protects albumin and IgG from lysosomal degradation, allowing these proteins to be recycled intact. 24: 196624: -198024: , 201324: . doi: 10.1681 The main function of the kidney is to filter plasma, while at the same time, retain the majority of plasma proteins. However, a certain fraction of plasma proteins inevitably passes the glomerular filtration barrier. The most abundant and most studied plasma protein, albumin, is produced at a rate of about 15 g per day in humans. 1 In the renal glomerulus, the albumin sieving coefficient (i.e., the transport rate of albumin across the glomerular filter in relation to water) has been estimated to be below 0.001. [2][3][4] In more recent studies using intravital microscopy, the albumin sieving coefficient has been estimated to be significantly higher, although this result is still controversial. 5-7 Thus, even when assuming a tight renal filtration barrier, significant amounts of albumin pass the glomerular filterroughly in the range of 1 g per day in healthy humans, J Am Soc Nephrol

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

“…2,4 The present study had three main objectives. First, to determine whether an acute systemic albumin load, achieved by two intraperitoneal albumin injections, resulting in increased albumin excretion, causes detectably increased glomerular filtration of albumin.…”

“…Because FcRn is the only known transcytotic albumin receptor, and rat FcRn binds bovine albumin with reduced affinity, we utilized rat albumin for these studies. 4,7,16,46 Species differences in albumin and IgG binding to FcRn are well documented and may contribute to some of the variability reported in protein overload studies. The binding affinity for megalin/cubilin for different albumins has yet to be determined but this receptor has been shown to only target albumin to lysosomes.…”

“…This is supported by studies in knockout mice and more recently by some elegant studies using transgenic mice and rat models by the Moeller group. 4,46 To identify possible pathways that could be participating in the reduced PT albumin uptake, quantitative two-dimensional gel electrophoresis (2DE) combined with mass spectrometry and pathway analysis was conducted on kidney cortex proteins from control and protein overload rats. The largest increase (1.83) was observed for albumin.…”

“…1 Recent data from several laboratories utilizing different approaches have delineated a role of proximal tubules (PTs) in regulation of albumin reabsorption and reclamation. 2 Furthermore, albumin transcytosis has been visualized in PT cells 3 and FcRn has been shown to mediate the transcytosis of albumin across PTCs, 4 as it is known to do for many other cell types. 2 Therefore, the present studies were conducted to begin differentiating and quantifying glomerular and PT contributions to albuminuria under physiologic and disease conditions.…”

New frontiers in intravital microscopy of the kidney

“…However, more recent intravital imaging studies have challenged this paradigm, with the observation that fluorescently labelled albumin injected systemically rapidly appears in the apical part of cells in the proximal tubule, implying that tubular reuptake plays a far more important role than previously appreciated [28]. It has also been proposed, partly on the basis of imaging studies, that albumin may be trafficked directly across proximal tubule cells and back into the blood stream [29,30]. These surprising findings have huge implications for clinical practice and have inevitably generated much controversy; the picture is further complicated by the fact that different groups using the same imaging techniques have reported very different values for the glomerular sieving coefficient [31,32].…”