Junko Takagi

Octreotide-induced suppression of the hyperglycemic response to neostigmine or bombesin: relationship to hypothalamic noradrenergic drive

Neostigmine (cholinesterase inhibitor) or bombesin, when injected into the third cerebral ventricle of awake rat, dose-dependently increased serum glucose with the simultaneous rise in hypothalamic noradrenergic neuronal activity (NAA). Co-administration of octreotide with neostigmine or bombesin suppressed the hypothalamic NNA response with the simultaneous inhibition of the hyperglycemic response. There was a close relationship between hypothalamic NNA and serum glucose in these studies. On the basis of the concept that hypothalamic noradrenergic drive plays an important role in mediating the hyperglycemic response to stressful stimuli, the present findings suggest that the hyperglycemic response to neostigmine or bombesin is mediated via the interaction with hypothalamic noradrenergic neurons.

Histologic study of age-related change in the posterior pituitary gland focusing on abnormal deposition of tau protein

We studied histologic findings of age‐related change in the posterior pituitary gland focusing specifically on abnormal deposition of tau protein. Posterior pituitary glands from a total of 201 patients with mean age of 72, range 15 to 100 years, were dissected at autopsy, and semiquantitative analysis of tau protein deposition in the posterior pituitaries was performed. We confirmed that tau protein deposition in the posterior pituitary appears histologically as either a ‘thread‐like’ or ‘dot’ form. In double staining using an anti‐neurofilament antibody and Gallyas‐Braak staining, Gallyas‐Braak‐positive structures were located in the neurite. The grade and the frequency of tau protein deposition were increased in accord with aging. An interrelation was observed between tau protein deposition in the brain and that in the posterior pituitary. In tauopathy diseases, tau protein deposition in the posterior lobe is advanced compared to that in non‐tauopathy diseases. The level of tau protein deposition in the hypothalamus was compared semi‐quantitatively with that in the posterior pituitary, and the levels correlated well. We suggest that in the posterior pituitary of elderly people, high frequency of occurrence of deposition of abnormal tau protein in the neurites may cause dysfunction of the pituitary gland.

Urinary β-2 Microglobulin Levels Sensitively Altered in an Osteomalacia Patient Receiving Add-on Adefovir Dipivoxil Therapy for Hepatitis B Virus Infection.

Adefovir dipivoxil (ADV) is effective for hepatitis B virus (HBV) infection; however, ADV may provoke renal injury resulting in osteomalacia, and this side effect is seldom recognized until bone fractures emerge. We herein present a 66-year-old woman with HBV infection who received ADV for 6 years. Although she exhibited no sign of bone fractures, her urinary β-2 microglobulin (β2MG) level increased to 83,837 μg/L and scintigraphy revealed minimal fractures of the third rib. ADV was subsequently reduced and her urinary β2MG rapidly fell to 3,637 μg/L. Conversely, her urinary N-acetyl-β-D-glucosaminidase, and serum phosphate, alkaline phosphatase levels did not respond.

A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome

Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.

Glomerular basement membrane (GBM) abnormalities are worth pursuing

Historically, the glomerular basement membrane (GBM) has drawn the attention of nephrologists for more than three decades because the amassed evidence clearly indicated that it functioned as the filtration barrier that keeps albumin in the circulation [1, 2]. A paradigm shift occurred in 1998, when a slit membrane protein, nephrin, was identified as the responsible gene in patients with congenital nephrotic syndrome [3]. After the discovery of nephrin, the prevailing view was that slit membranes located in the adjoining foot processes of podocytes contain a pore responsible for preventing the passage of plasma proteins [2]. Proteinuria, however, is a very prevalent phenomenon observed in a variety of abnormalities. Subsequent evidence showed that abnormalities in the GBM could also lead to massive proteinuria and kidney failure [4]. Thus, like the swinging of a pendulum [2], the GBM has re-captured the attention of nephrologists. There is another attractive aspect of the GBM. It is not a cellular component but an extracellular matrix (ECM). The ECM is fully capable of providing biochemical support to the surrounding cells and modulating cellular activities, which makes it far from being simply a structural support consisting of glycoproteins and sugars (polysaccharides) [5]. Understanding the idea of ‘cell–matrix interaction as a regulator of cellular behavior’ [6–8] is important in understanding the theoretical background of why GBM abnormalities are subjects of study. Impressively, mutations of the genes encoding major GBM molecules lead to glomerular diseases. For example, collagen type IV is the most abundant glycoprotein of the GBM. Six different a-chains of type IV collagen are known. They include the a1(IV), a2(IV), a3(IV), a4(IV), a5(IV), and a6(IV) chains, which are encoded by the COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, and COL4A6 genes, respectively [9]. A mutation in any one of the COL4A3, COL4A4, or COL4A5 genes causes Alport syndrome [10]. In this issue of Clinical and Experimental Nephrology, Masuda and colleagues report on the GBM abnormalities observed in 50 patients with IgA nephropathy who underwent renal biopsy [11]. In their effort to elucidate the morphologic changes of the GBM, they immunostained a2(IV) and a5(IV) in the same 3 lm-thick frozen sections and found various alterations in the expression of these chains. Although immunostaining for the a2(IV) and a5(IV) chains was performed in previous studies dealing with acquired glomerulonephritis [12], membranous nephropathy [13], and IgA nephropathy [14, 15], none of them clearly showed reduced a5(IV) expression and definitely increased a2(IV) expression in the thickened GBM, as Masuda and colleagues have done. Importantly, this pattern of expression partially resembles that in X-linked and autosomal recessive Alport syndrome in which analyses of homo-trimeric and hetero-trimeric combinations of the alpha chains have been performed [16, 17]. In Alport syndrome, the normal collagen IV network in the GBM, which consists primarily of cross-linked a3, a4, a5(IV) protomers [9, 16], is completely lost, and a compensatory This comment refers to the article available at doi:10.1007/s10157014-1008-8.