Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Abstract

Evidence from multiple studies supports the concept that both glomerular filtration and proximal tubule (PT) reclamation affect urinary albumin excretion rate. To better understand these roles of glomerular filtration and PT uptake, we investigated these processes in two distinct animal models. In a rat model of acute exogenous albumin overload, we quantified glomerular sieving coefficients (GSC) and PT uptake of Texas Red-labeled rat serum albumin using two-photon intravital microscopy. No change in GSC was observed, but a significant decrease in PT albumin uptake was quantified. In a second model, loss of endogenous albumin was induced in rats by podocyte-specific transgenic expression of diphtheria toxin receptor. In these albumin-deficient rats, exposure to diphtheria toxin induced an increase in albumin GSC and albumin filtration, resulting in increased exposure of the PTs to endogenous albumin. In this case, PT albumin reabsorption was markedly increased. Analysis of known albumin receptors and assessment of cortical protein expression in the albumin overload model, conducted to identify potential proteins and pathways affected by acute protein overload, revealed changes in the expression levels of calreticulin, disabled homolog 2, NRF2, angiopoietin-2, and proteins involved in ATP synthesis. Taken together, these results suggest that a regulated PT cell albumin uptake system can respond rapidly to different physiologic conditions to minimize alterations in serum albumin level. 27: 482-494, 201627: 482-494, . doi: 10.1681 While the clinical relevance of proteinuria, and especially albuminuria, has been well documented, the quantitative and mechanistic significance of different components to albumin excretion remains an area of considerable excitement and debate. 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. This understanding is important because before appropriate therapies can be developed to modulate albuminuria, the structural, functional and mechanistic characterization need to be better understood and interrelated. J Am Soc Nephrol

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