Makiko Nakayama

Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss

Collapsing focal segmental glomerulosclerosis (cFSGS) is a progressive kidney disease characterized by glomerular collapse with epithelial hyperplasia. Here we used a transgenic mouse model of cFSGS with immunotoxin-induced podocyte-specific injury to determine the role for Notch signaling in its pathogenesis. The mice exhibited progressive loss of podocytes and severe proteinuria concomitant with histological features of cFSGS. Hyperplastic epithelium was negative for genetic podocyte tags, but positive for the parietal epithelial cell marker claudin-1, and expressed Notch1, Jagged1, and Hes1 mRNA and protein. Enhanced Notch mRNA expression induced by transforming growth factor-β1 in cultured parietal epithelial cells was associated with mesenchymal markers (α-smooth muscle actin, vimentin, and Snail1). Notch inhibition in vitro suppressed these phenotypic transcripts and Notch-dependent cell migration. Moreover, Notch inhibition in vivo significantly decreased parietal epithelial cell lesions but worsened proteinuria and histopathology in our cFSGS model. Thus, aberrant Notch1-mediated parietal epithelial cell migration with phenotypic changes appears to underlie the pathogenesis of cFSGS. Parietal epithelial cell hyperplasia may also represent an adaptive response to compensate for a disrupted filtration barrier with progressive podocyte loss.

Severe Alport syndrome in a young woman caused by a t(X;1)(q22.3;p36.32) balanced translocation

The course of renal involvement and hearing loss is much milder in most female X-linked Alport syndromes than in male patients. We examined the molecular mechanism of development of the disease in a female patient with severe Alport syndrome. The patient showed heavy proteinuria, hematuria, neurosensory hearing loss and primary amenorrhea. Renal biopsy findings of electron microscopy and immunostaining of the α5 chain of type IV collagen indicated a female X-linked Alport syndrome. G-banding chromosomal analysis showed a t(X;1)(q22.3;p36.32) balanced translocation. Analysis of the collagen type IV (COL4A5) gene by genomic DNA sequencing, complementary DNA (cDNA) sequencing and multiplex ligation-dependent probe amplification assay showed no mutations or deletions/duplications of the gene. However, fluorescence in situ hybridization using the probes for exon 1 and exon 51 of the COL4A5 gene showed disruption of one copy of the gene. Replication R-banding chromosomal analysis indicated preferential inactivation of the normal X chromosome. This is the first report of severe Alport syndrome in a female patient carrying a balanced translocation between the chromosome X and 1 producing the disruption of one copy of COL4A5 gene and silencing of the other copy because of preferential inactivation of the normal X chromosome. Chromosomal abnormalities should be considered in female patients with severe forms of Alport syndrome.

Phenotype variability in nephrogenic diabetes insipidus due to p.D85N mutation in the arginine vasopressin receptor 2 gene

To the Editor Congenital nephrogenic diabetes insipidus (NDI) is a hereditary renal disease involving defective renal responses to arginine vasopressin (AVP). Approximately 90% of congenital NDI patients are males with mutations in the arginine vasopressin receptor 2 (AVPR2) gene, which is located in chromosome region Xq28 (OMIM 304800), and an X-linked recessive mode of inheritance. The present study describes one large Japanese family with X-linked NDI caused by recurrent p.D85N of AVPR2 gene. The reported phenotype in patients carrying this mutation is usually mild. In this report, we show the first family showing that a hemizygous male proband and a homozygous female with this mutation presented with severe form of NDI. A boy aged 4 years 7 months was referred to us for re-evaluation of congenital NDI. He had suffered from polyuria and polydipsia since the early neonatal period. His urine osmolality was 64 mOsmol/kg and urine volume was >5 L/day. During a 20 mg 1-deamino-8-D-arginine-

A case of de novo glomerulonephritis with electron-dense deposits following renal transplantation

Abstract:  We present here a case of de novo glomerulonephritis (GN) two yr after kidney transplantation. The patient was a 13‐yr‐old girl who had renal insufficiency because of bilateral hypoplastic kidneys. She received a renal allograft from her father at the age of 11 yr. Immunosuppressive treatment was started with tacrolimus, mizoribine (MZB), basiliximab, and methylprednisolone (mPSL). There were no findings of GN at the one‐h biopsy (first biopsy). Two yr after transplantation, she showed proteinuria, hematuria and increased serum creatinine level with no apparent trigger. The biopsy specimen (fourth) showed mesangial proliferative GN with electron‐dense deposits in a variety of regions and borderline changes indicating acute rejection. She was treated with mPSL pulse therapy, deoxyspergualin, replacement of MZB with mycophenolate mofetil, an increase of the mPSL dose, and candesartan. Her serum creatinine and urinary protein excretion levels improved after the treatment. One month later, she developed deterioration in her renal function again. Renal biopsy findings (fifth) were almost the same as the lesions observed in the fourth allograft biopsy. After she recovered from these episodes, she appeared to improve in clinical findings of GN. Protocol biopsies at three yr and five months after transplantation (sixth) showed no evidence of acute rejection, but we still observed the features of de novo GN. We could not resolve the underlying causes by reference to the clinical history and serological findings. We speculate that some kind of immunological reactions might be associated with the pathophysiology.