Secondary hyperparathyroidism, in which parathyroid hormone (PTH) is excessively secreted in response to factors such as hyperphosphataemia, hypocalcaemia, and low 1,25-dihydroxyvitamin D (1,25(OH)2D) levels, is commonly observed in patients with chronic kidney disease (CKD), and is accompanied by high levels of fibroblast growth factor 23 (FGF23). However, the effect of FGF23 on the parathyroid glands (PG) remains controversial. To bind to FGF receptors, FGF23 requires αKlotho, which is highly expressed in the PG. Here, we examined the effects of Fgfr1–3, αKlotho, or Fgfr1–4 ablation specifically in the PG (conditional knockout, cKO). When mice with early to mid-stage CKD with and without cKO were compared, plasma concentrations of calcium, phosphate, FGF23, and 1,25(OH)2D did not change significantly. In contrast, plasma PTH levels, which were elevated in CKD mice, were significantly decreased in cKO mice. PG from CKD mice showed augmentation of cell proliferation, which was significantly suppressed by cKO. Parathyroid tissue cultured for 4 days showed upregulation of PTH secretion and cell proliferation in response to FGF23. Both these effects were inhibited by cKO. These findings suggest that FGF23 is a long-term inducer of parathyroid cell proliferation and PTH secretion, and is one cause of secondary hyperparathyroidism in CKD.

Fibroblast growth factor 23 (FGF23) plays critical roles in phosphate handling and vitamin D metabolism in the kidney. However, the effector cells of FGF23 in the kidney remain unclear. αKlotho, a putative enzyme possessing β-glucuronidase activity and also a permissive co-receptor for FGF23 to bind to FGF receptors (FGFRs), is expressed most abundantly in distal convoluted tubules, whereas it is expressed modestly in proximal tubules. Key molecular players of phosphate homeostasis and vitamin D-metabolizing enzymes are known to localize in proximal tubules. To clarify the direct function of FGF23 on proximal tubules, we ablated αKlotho or Fgfr1–4 genes specifically from these tubules using the Cre-loxP-mediated genetic recombination. Both conditional knockout mouse lines showed similar phenotypes that resembled those of systemic αKlotho or Fgf23 knockout mice. Compared with control mice, they showed significantly elevated levels of plasma phosphate, FGF23 and 1,25-dihydroxyvitamin D, ectopic calcification in the kidney and aging-related phenotypes like growth retardation, osteoporosis and shortened lifespan. These findings suggest that the primary function of FGF23 on mineral metabolism is mediated through αKlotho/FGFR co-receptors expressed in proximal tubular cells, and that the putative enzymatic function of αKlotho in the proximal tubule has a minor role in systemic mineral metabolism.

In Mongolian gerbils, bilateral common carotid artery occlusion (BCCAO) for several minutes induces ischemia, due to an incomplete circle of Willis, resulting in delayed neuronal cell death in the Cornet d'Ammon 1 (CA1) region of the hippocampus. Neuronal cell death in the hippocampus and changes in behavior were examined after BCCAO was performed for 5 min in the gerbils. One day after BCCAO, the pyramidal neurons of the CA1 region of the hippocampus showed degenerative changes (clumped chromatin in nuclei). At 5 and 10 days after BCCAO, extensive neuronal cell death was observed in the hippocampal CA1 region. Cognitive performance was evaluated by using the radial maze and passive avoidance tests. In the radial maze test, which examines win-stay performance, the number of errors was significantly higher in ischemic gerbils than in sham-operated gerbils on days 1 and 2 post-operation. In the passive avoidance test, the latency and freezing times were significantly shorter in ischemic gerbils than in sham-operated gerbils on the days 1, 2, and 4–6 post-operation. These results indicate that transient forebrain ischemia impairs cognitive performance, even immediately after the ischemic insult when there are only subtle signs of neuronal cell death.

Abstract. Nitric oxide synthase (NOS) is a key regulator of angiogenesis and embryogenesis in the mammalian reproductive process. Here, we attempted to clarify the expression and localization of inducible and endothelial NOS (iNOS and eNOS) in the developing rabbit placenta. Real-time RT-PCR analysis indicated that iNOS mRNA was significantly upregulated till the complete development of the placenta (d18), and then significantly decreased at the end of fetal growth stage (d28) during successful pregnancy. The eNOS mRNA was also enhanced in the pregnant uteri and gradually decreased near the term of pregnancy. Western blot analysis also showed elevation of the iNOS and eNOS protein levels during the course of successful pregnancy till the functional maturation of the placenta (d18). Immunohistochemical study revealed distinct localizations of iNOS along the radial arteries and eNOS at the spiral arteries and arterial sinuses in the developing placenta. This may reflect that iNOS and eNOS participate in pregnancy success through placentation-specific vascular formation and by supporting adequate blood circulation in the rabbit placenta. Key words: eNOS, iNOS, Rabbit placenta, Vascular formation (J. Reprod. Dev. 58: [231][232][233][234][235][236] 2012) I n pregnant mammals, the placenta acts as exchange interface for nutrients and waste products between the fetal and maternal circulation. The placenta is a very fast growing tissue with corresponding high metabolic demand from the embryo or fetus that requires an active blood supply and rapid vascular development [1][2][3]. Failure of placental growth during early and mid pregnancy is directly associated with inadequate uterine and umbilical blood flow, which adversely affects transportation of fetal nutrients [4]. Extensive increase of the transplacental exchange during the last half of gestation is closely dependent upon the dramatic growth of the vascular architecture and the resultant large volume of uterine and umbilical blood flow [1].Nitric oxide (NO), a multifunctional biomolecule, is produced from the essential amino acid L-arginine via nitric oxide synthase (NOS), which is classified into the calcium-independent or constitutive calcium/calmodulin-sensitive isoforms. The former is represented by inducible NOS (iNOS), and the latter is represented by the endothelial and neuronal NOS (eNOS and nNOS) [5]. NO plays crucial roles in the mediation of a wide variety of physiological processes including vasodilation, angiogenesis, platelet aggression, immune functions, connective tissue remodeling and smooth muscle activity [6]. iNOS and eNOS are known to dynamically regulate normal physiological events during successful pregnancy such as ovulation, implantation, trophoblast invasion, placental formation, fetal development and delivery [7][8][9].In the developing placenta, specific vascular formation occurs through the processes of destruction of preexisting vessels, de novo angiogenesis and convergence of blood path in association with the invitation of plenty ...

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