Takahito Moriyama · Kazunori Karasawa · Kosaku Nitta
Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan
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Abstract
Background: In the traditional theory of albuminuria, small amounts of albumin pass through the fenestrae in glomerular endothelial cells, then through the slit membrane in the gaps between foot processes of glomerular epithelial cells. In the novel theory, large amounts of albumin pass through glomerular capillaries and are taken up by megalin and cubilin receptors on tubular epithelial cells. These etiologies of urinary albumin excretion are still controversial, and the details of albumin passage through the three layers of glomerular capillaries (glomerular endothelial cells, basement membrane, and epithelial cells) have never been entirely elucidated. Summary: Recent advances in basic research have shown that caveolae, which are cell invaginations located on the surface of both glomerular endothelial and epithelial cells, play pivotal roles in the endocytosis, transcytosis, and exocytosis of albumin. Albumin enters into glomerular endothelial and epithelial cells through caveolae; subsequent transcytosis of albumin is not actin- or microtubuledependent in glomerular endothelial cells, but is actin-dependent in glomerular epithelial cells. Exocytosis of albumin in glomerular endothelial cells occurs via early endosomes through a process that bypasses other endosome-associated organelles. In contrast, exocytosis of albumin in glomerular epithelial cells occurs via early endosomes through a process that results in lysosomal degradation of some albumin particles. Key Messages: This caveolae-dependent pathway may provide a new pathophysiology for albumin passage through glomerular endothelial and epithelial cells, leading to a new etiology for urinary albumin excretion that connects both traditional and novel theories of albuminuria.
© 2018 S. Karger AG, Basel
The Roles of Caveolae
Caveolae are 50–80 nm, flask-shaped, membrane invaginations that were originally identified as very small pit-like depressions on the cell membrane of microvilli in 1955 [1]. Caveolae are primarily located on vascular endothelial cells, smooth muscle cells, cardiomyocytes, and adipocytes; they are enriched with cholesterol, sphingolipids, and glycolipids, and are structured by scaffolding proteins known as caveolin. There are three caveolin proteins encoded by independent genes, which are identified as caveolin-1 (Cav-1), caveolin-2, and caveolin-3. Cav-1 and caveolin-2 are co-expressed on a variety of cells, while caveolin-3 is solely expressed by muscle cells [2, 3]. Cav-1 is expressed as 2 isoforms: Cav-1α contains 178 amino acids and Cav-1β contains 147 amino acids, lacking the N-terminal 31 amino acids of Cav-1α. These isoforms arise from 2 different mRNA transcripts of the same gene. Both isoforms of Cav-1 are membrane proteins with a 33-amino-acid hydrophobic domain that constitutes a hairpin loop; the N-termini and C-termini extend into the cytoplasm. Cav-1 proteins assemble as disk-shaped oligomers around the scaffolding domain and are anchored by a portion of the palmitoylated C-terminal within the cell membrane [2, 3]. The roles of caveolae are diverse and comprise adjustment of endothelial nitric oxide synthesis and calcium signaling; regulation of intracellular signal transduction, including receptors, such as G-protein coupled receptors, epidermal growth factor receptors, insulin receptors, platelet-derived growth factor receptors (PDGF-R), vascular endothelial growth factor receptors, activin receptor-like kinase, transforming growth factor-β, ras-mitogen activated protein kinase, Src family tyrosine kinases, various forms of protein kinase A, and various forms of protein kinase C (Table 1) [4, 5]; and to internalize and transport cholesterol, proteins, insulin, and toxins that play pivotal roles in a variety of diseases (e.g., viral infections, inflammation, cancer, cardiovascular disease, atherosclerosis, myopathies, and diabetes [6–9]). In the kidney, caveolae are expressed by glomerular endothelial cells (Fig. 1a), epithelial cells (Fig. 1a), mesangial cells, and tubular epithelial cells. However, the specific roles of caveolae in the kidney cells are not yet known.
The Roles of Caveolae in the Kidney
A variety of roles for caveolae in the kidney have been reported in previous studies. In rat kidneys exhibiting anti-Thy-1 nephritis, Cav-1 was highly expressed by glomeruli; Cav-1 on glomerular mesangial cells was suspected to play a role in the pathogenesis of mesangial proliferative glomerular disease through PDGF signaling [10]. In contrast, overexpression of Cav-1 in mesangial cells suppressed basic fibroblast growth factor-induced and PDGF-induced activation of p42/44 mitogen activated protein kinase, Raf-1 and extracellular signal-regulated protein kinase, thereby suppressing mesangial cell proliferation [11]. Exposure to TGFβ and high glucose increased fibronectin expression and RhoA activation through Cav-1 phosphorylation, whereas suppression of Cav-1 prevented an increase in fibronectin expression [12, 13]. However, the detailed roles of Cav-1 in mesangial cells are still intensely debated. In the parietal epithelial cells of Bowman’s capsule in normal kidney, Cav-1 is strongly expressed; however, in pediatric patients with focal segmental glomerulosclerosis and lupus nephritis, Cav-1 expression decreased as a response to cellular reconstruction [14]. In a study of acute kidney injury, Cav-1 was expressed in injured proximal tubules that exhibited loss of basement membrane, as well as in apoptotic cells [15], and its expression was correlated with the induction and maintenance phases of acute kidney injury [16]. In cases of obstructive nephritis, Cav-1 expression by both proximal tubule epithelial cells and collecting duct epithelial cells resulted in the enhancement of angiotensin II, decrease in endothelial nitric oxide synthesis, and increase in the severity of tubulointerstitial injury [17]. Further, BK virus, which induces viral nephritis after renal transplantation, was observed to enter into tubular proximal epithelial cells through caveolae, facilitating its ultimate replication in host cells [18]. As discussed here, the detailed roles of caveolae in tubular epithelial cells continue to be unclear.
Table 1. Caveolae-associated signaling molecules and transduction proteins
| Receptors G protein coupled receptors (adrenergic, muscarinic, opioid, angiotensin II, adenosine, bradykinin, endothelin, serotonin, etc.) Transforming growth factor-β receptors Tyrosine kinase (insulin, EGF-R, PDGF-R, VEGF-R) |
|
Interacting proteins
eNOS
Src
Ras-MAP kinase
Protein kinase A
Protein kinase Cα
MEK/ERK
Phospholipase D1
|