Novel routes of albumin passage across the glomerular filtration barrier

Abstract

Albuminuria is a hallmark of kidney diseases of various aetiologies and an unambiguous symptom of the compromised integrity of the glomerular filtration barrier. Furthermore, there is increasing evidence that albuminuria per se aggravates the development and progression of chronic kidney disease. This review covers new aspects of the movement of large plasma proteins across the glomerular filtration barrier in health and disease. Specifically, this review focuses on the role of endocytosis and transcytosis of albumin by podocytes, which constitutes a new pathway of plasma proteins across the filtration barrier. Thus, we summarize what is known about the mechanisms of albumin endocytosis by podocytes and address the fate of the endocytosed albumin, which is directed to lysosomal degradation or transcellular movement with subsequent vesicular release into the urinary space. We also address the functional consequences of overt albumin endocytosis by podocytes, such as the formation of pro-inflammatory cytokines, which might eventually result in a deterioration of podocyte function. Finally, we consider the diagnostic potential of podocyte-derived albumin-containing vesicles in the urine as an early marker of a compromised glomerular barrier function. In terms of new technical approaches, the review covers how our knowledge of the movement of albumin across the glomerular filtration barrier has expanded by the use of new intravital imaging techniques.

Intracellular transcytosis of albumin in glomerular endothelial cells after endocytosis through caveolae

“…A very recent report indicated that angiotensin‐II infusion induced albumin transcytosis through glomerular epithelial cells in the healthy rat kidney and analysis with a multi‐photon scope showed that 86% of the endocytosed albumin was moved via transcytosis to the urinary space (Schieß et al, ). Together, these reports strengthened the evidence for a transcellular pathway across glomerular epithelial cells (Castrop & Schieß, ). In vascular endothelial cells, albumin entered cells through caveolae (Li et al, ; Pascariu, Bendayan, & Ghitescu, ; Schubert et al, ) and was transported to the early endosomes, but did not reach the GA (Aoki, Hagiwara, Matsuzaki, Suzuki, & Takata, ) or lysosomes (Vogel, Minshall, Pilipović, Tiruppathi, & Malik, ).…”

A New Pathogenesis of Albuminuria: Role of Transcytosis

“…Furthermore, insufficient transcytosis by dysfunctional PTCs also contributes to albuminuria. Under physiological conditions PTCs can reabsorb, transcytose Receptor-mediated albumin transcytosis in GECs has been proven to be involved in the formation of albuminuria [34] Podocytes Podocytes have the ability of albumin endocytosis and transcytosis [35,36,44,45,47,50,51,53] PTCs Defects of rat PTCs in endocytosis and transcytosis are involved in the pathogenesis of albuminuria [37,46,57] and process filtered albumin. Albumin is internalized to PTCs via megalin-cubilin-mediated, clathrin-dependent endocytosis.…”

“…Increasing evidence has shown that podocytes are able to endocytose and transcytose proteins [35,36,44,45]. Previous studies showed that cultured podocytes internalized albumin via transcytosis [36,[46][47][48].…”

Diabetic nephropathy: is it always there? Assumptions, weaknesses and pitfalls in the diagnosis

“…[62][63][64] Conversely, statins have been shown to reduce albumin endocytosis by PTCs and may enhance albuminuria. 65,66 Taking all the above into account, it could be postulated that the amount of albumin detected in a spot urine sample, which is the criterion in order to characterize a patient as having DN or not, is the net result of several parameters that are both patient related (degree of glomerular damage, proximal tubular integrity, serum albumin levels), but also health professionals related (use of therapeutic agents that influence glomerular filtration of albumin such as ACE-inh/ARBs or statins, or tubular processing of the filtered albumin like SGLT2 inhibitors, as well as the degree of hypertension, glycemic and lipids control in general).…”