Decreased Podocyte Vesicle Transcytosis and Albuminuria in APC C-Terminal Deficiency Mice with Puromycin-Induced Nephrotic Syndrome

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.

GDF-15 Suppresses Puromycin Aminonucleoside-Induced Podocyte Injury by Reducing Endoplasmic Reticulum Stress and Glomerular Inflammation

“…In support of our data, Pod-Sec63/Xbp1 double-knockout mice did not exhibit different autophagosomal activity but still displayed severe ER stress [36]. This finding is surprising, considering that podocytes generally exhibit relatively high basal autophagy compared to other cell types [61,62]. Additionally, enhanced autophagy has been observed in glomerulopathies in humans, as indicated by elevated kidney ER stress in patients with MCD or FSGS [63,64].…”

Annexin A1 may contribute to the morphological changes in podocytes by mediating endocytic vesicle fusion and transport via promotion of SNARE assembly in idiopathic membranous nephropathy

“…We observed vesicles in podocytes from IMN patients with electron microscopy and found that the numbers of intracellular vesicles in podocytes from IMN patients were significantly increased (Figure 1). A previous study has reported that suppression of podocyte vesicle transport is associated with reduced albuminuria in nephritic syndrome 15 . Moreover, SNARE‐associated vesicular insertion into the plasma membrane causes podocyte actin remodelling and proteinuria 6 .…”

“…Vesicle formation plays an important role in maintaining the structure of foot processes in glomerular podocytes 22 . However, increased vesicle transcytosis is associated with foot process effacement in podocytes in nephrotic syndrome 15 . In a rat model of nephrotic syndrome induced by puromycin aminonucleoside, accumulation of blue‐labelled albumin endocytic vesicles is observed in podocytes 23 .…”

“…22 However, increased vesicle transcytosis is associated with foot process effacement in podocytes in nephrotic syndrome. 15 In a rat model of nephrotic syndrome induced by puromycin aminonucleoside, accumulation of blue-labelled albumin endocytic vesicles is observed in podocytes. 23 Enhanced endocytosis and transcytosis lead to increased vesicles, resulting in the migration of albumin-containing vesicles from the glomerular capillaries to the tips of the podocytes F I G U R E 5 Overview of the biological processes of the DEGs from GSE115857.…”

“…A previous study has reported that suppression of podocyte vesicle transport is associated with reduced albuminuria in nephritic syndrome. 15 Moreover, SNARE-associated vesicular insertion into the plasma membrane causes podocyte actin remodelling and proteinuria. 6 Thus, the increased numbers of vesicles in podocytes may contribute to morphological changes in podocytes in IMN.…”