Abstract
In minimal change nephrotic syndrome, podocyte vesicle transport is enhanced. Adenomatous polyposis coli (APC) anchors microtubules to cell membranes and plays an important role in vesicle transport. To clarify the role of APC in vesicle transport in podocytes, nephrotic syndrome was induced by puromycin amino nucleoside (PAN) injection in mice expressing APC1638T lacking the C-terminal of microtubule-binding site (APC1638T mouse); this was examined in renal tissue changes. The kidney size and glomerular area of APC1638T mice were reduced (p = 0.014); however, the number of podocytes was same between wild-type (WT) mice and APC1638T mice. The ultrastructure of podocyte foot process was normal by electron microscopy. When nephrotic syndrome was induced, the kidneys of WT+PAN mice became swollen with many hyaline casts, whereas these changes were inhibited in the kidneys of APC1638T+PAN mice. Electron microscopy showed foot process effacement in both groups; however, APC1638T+PAN mice had fewer vesicles in the basal area of podocytes than WT+PAN mice. Cytoplasmic dynein-1, a motor protein for vesicle transport, and α-tubulin were significantly reduced in APC1638T+PAN mice associated with suppressed urinary albumin excretion compared to WT+PAN mice. In conclusion, APC1638T mice showed reduced albuminuria associated with suppressed podocyte vesicle transport when minimal change nephrotic syndrome was induced.
Highlights
The first electron microscopy observation of glomerulus in 1955 prompted several theories concerning glomerular filtration involving detection of the slit membrane as a glomerular filtration barrier [1] and transepithelial transport via podocyte vesicles [2]
The observation of a zipper-like structure in the slit membrane [4] followed by the detection of nephrin as a slit membrane molecule [5] confirmed the concept that albumin leaks through the slit membrane pores in nephrotic syndrome [6,7]
Glomerular podocytes contain similarities to neurons and express PSD93 [33], so in the present study, we investigated the morphological changes in podocyte microtubule and vesicle transport in APC1638T mice with puromycin amino nucleoside (PAN)-induced minimal change nephrotic syndrome (MCNS) and discussed the importance of podocyte vesicle transport as a mechanism of selective albuminuria
Summary
The first electron microscopy observation of glomerulus in 1955 prompted several theories concerning glomerular filtration involving detection of the slit membrane as a glomerular filtration barrier [1] and transepithelial transport via podocyte vesicles [2]. The concept of transepithelial transport via podocyte vesicles has long been neglected. The observation of a zipper-like structure in the slit membrane [4] followed by the detection of nephrin as a slit membrane molecule [5] confirmed the concept that albumin leaks through the slit membrane pores in nephrotic syndrome [6,7]. The mystery of the glomerular filtration barrier (GFB) is why it does not clog [10] when filtering 3 g of albumin daily in the primary urine, even under normal conditions [11]. Gel hypotheses and electrokinetic models have been proposed to solve the mystery of GFB clogging [10,12], but not enough attention has been paid to the mechanism of transcytosis in podocytes
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