Mechanisms of Glomerular Albumin Filtration and Tubular Reabsorption

Tojo, Akihiro; Kinugasa, Satoshi

doi:10.1155/2012/481520

Cited by 202 publications

(155 citation statements)

References 68 publications

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“…[30][31][32][33][34][35][36][37] However, in all of these studies albuminuria was not markedly increased, thus supporting recent evidence for other mechanisms having an active role in albumin retrieval occurring in PTCs. FcRn, the only albumin transcytotic receptor yet identified, is concentrated in the apical region of the PTCs as shown in Figure 4B.…”

Section: Discussionsupporting

confidence: 82%

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Wagner

Campos-Bilderback

Chowdhury

et al. 2016

Journal of the American Society of Nephrology

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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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Section: Discussionsupporting

confidence: 82%

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Wagner

Campos-Bilderback

Chowdhury

et al. 2016

Journal of the American Society of Nephrology

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“…Nonbound APOL1 is small enough (42 kD) to be filtered across the glomerular barrier and would be available for reabsorption by kidney cells, similar to albumin (67 kD), which has also been detected in podocytes 14 and PTCs. 15 The APOL1 concentrations in media to which our cell lines were exposed were far lower than those previously reported by Duchateau in serum (5-10 mg/ml) 16 and estimated in our studies (15 mg/ml). Assuming that #5% of serum APOL1 exists in a lipid-free form, as is the case for APOA1, 17,18 we estimate that approximately 0.75 mg/ml APOL1 could potentially cross the glomerular filtration barrier.…”

Section: Discussioncontrasting

confidence: 59%

Localization of APOL1 Protein and mRNA in the Human Kidney

Ma¹,

Shelness²,

Snipes³

et al. 2015

Journal of the American Society of Nephrology

118

115

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Although APOL1 gene variants are associated with nephropathy in African Americans, little is known about APOL1 protein synthesis, uptake, and localization in kidney cells. To address these questions, we examined APOL1 protein and mRNA localization in human kidney and human kidney-derived cell lines. Indirect immunofluorescence microscopy performed on nondiseased nephrectomy cryosections from persons with normal kidney function revealed that APOL1 protein was markedly enriched in podocytes (colocalized with synaptopodin and Wilms' tumor suppressor) and present in lower abundance in renal tubule cells. Fluorescence in situ hybridization detected APOL1 mRNA in glomeruli (podocytes and endothelial cells) and tubules, consistent with endogenous synthesis in these cell types. When these analyses were extended to renal-derived cell lines, quantitative RT-PCR did not detect APOL1 mRNA in human mesangial cells; however, abundant levels of APOL1 mRNA were observed in proximal tubule cells and glomerular endothelial cells, with lower expression in podocytes. Western blot analysis revealed corresponding levels of APOL1 protein in these cell lines. To explain the apparent discrepancy between the marked abundance of APOL1 protein in kidney podocytes observed in cryosections versus the lesser abundance in podocyte cell lines, we explored APOL1 cellular uptake. APOL1 protein was taken up readily by human podocytes in vitro but was not taken up efficiently by mesangial cells, glomerular endothelial cells, or proximal tubule cells. We hypothesize that the higher levels of APOL1 protein in human cryosectioned podocytes may reflect both endogenous protein synthesis and APOL1 uptake from the circulation or glomerular filtrate.

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“…Under normal physiological conditions, the nephron filters about 3 g of albumin per day and the proximal tubular cells are responsible for reabsorbing approximately 90% of this load. 63 Transgenic sickle mice models and longitudinal studies may help improve our understanding of the timing between hemoglobinuria, glomerular and tubular damage, and increases in urine concentrations of albumin and KIM-1.…”

Section: Discussionmentioning

confidence: 99%