• Journal of Periodontal and Implant Science
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• v.30 no.2
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• pp.359-374
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• 2000

Cyclosporine A(CsA) is a widely used immunosuppressant for transplant patients and is also used for the treatment of a wide variety of systemic diseases with immunologic disorders. However, its use is frequently limited because of complications such as nephrotoxicity or gingival hyperplasia. Although several hypotheses have been postulated for CsA-induced gingival hyperplasia, i.e. various cytokine effects of inflammatory cells, existence of plaque or CsA itself, but its pathogenesis is still unclear. For experimental chronic CsA toxicity, salt depletion has been shown to increased susceptibility of rodents to the effects of CsA, and this maneuver facilitates production of arteriolopathy and interstitial fibrosis in kidney that mimic the changes found in human. The purpose of this study was to evaluate pathogenesis of CsA-induced gingival hyperplasia by comparing changes between CsA administration groups of normal standard diet and those of low salt diet group. Specific pathogen-free, 20 to 25 days old(120 to 150 g), male Fisher-344 rats(KIST, Korea), 120 to 150g of body weight, were assigned to four groups of six animals each after one week of adaptation period for powder food. Group 1 received olive oil($300{\mu}l/g\;of\;diet$) with normal standard diet(0.4% of sodium)(NSD). Group 2 received CsA(Cypol-N, Jonggundang, Korea; $300{\mu}g/g\;of\;diet$) with normal standard diet(NSD+CsA). Group 3 received same amount of olive oil with low salt diet(0.05 % of sodium, Teklad Premier, U.S.A.)(LSD). Group 4 received same dose of CsA with low salt diet(LSD+CsA). Rats were pair fed and were sacrificed after six weeks. Renal histologic lesions associated with CsA, consisted of cortical interstitial fibrosis, tubular atrophy and hyalinization of arterioles and the impairment of renal function including increase of serum creatinine and decrease of glomerular filtration rate was more severe in low salt diet group. These were proved as the results of activated of renin-angiotensin system in the kidney by low salt condition. Meanwhile the degree of gingival hyperplasia at incisor and molar tooth was less severe in low salt diet group compared with normal sodium diet group. Hyperplastic gingiva showed mild epithelial hyperplasia and expanded underlyng stroma which consisted of matrix increasement, capillary proliferation and dilatation. While the number and the activation of fibroblasts were increased, inflammatory cells were rare in the stroma. The immunohistochemistry for TGF-${\beta}_1$ in the kidney and gingiva revealed stronger positive in LSD+CsA in kidney but in gingiva of NSD+CsA. These results suggested followings; Gingival hyperplasia can be developed without inflammatory cells infiltration and seemed not induced by CsA by itself. The major role for gingival hyperplasia by CsA would be the secondary effect of TGF-${\beta}$, which maybe upregulated by CsA administration. Low salt diet can attenuate this hyperplasia perhaps by decreasing the activation of $TGF-{\beta}$.

• Applied Microscopy
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• v.23 no.2
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• pp.27-40
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• 1993

This study was taken to examine the light microscopic and ultrastructural changes of gill and kidney of female tilapia{Oreochromis niloticus) adapted in 0%o, 10%o, 20%o, and 30%o salt concentrations, respectively, by light, scanning and transmission electron microscope. The results obtained in these experiments were summarized as follows: Gill chloride cell hyperplasia, gill lamellar epithelial separation, kidney glomerular shrinkage, blood congestion in kidneys and deposition of hyalin droplets in kidney glomeruli, tubules were the histological alterations in Oreochromis niloticus. Incidence and severity of gill chloride cell hyperplasia rapidly increased together with increase of salinity, and the number of chloride cells in gill lamellae rapidly increased in response to high external NaCl concentrations. The ultrastructure by scanning electron microscope(SEM) indicated that the gill secondary lamella of tilapia(Oreochromis niloticus) exposed to seawater, were characterized by rough convoluted surfaces during the adaptation. Transmission electron microscopy(TEM) indicated that mitochondria in chloride cells exposed to seawater, were both large and elongate and contained well-developed cristae. TEM also showed the increased chloride cells exposed to seawater. The presence of two mitochondria-rich cell types is discussed with regard to their possible role in the hypoosmoregulatory changes which occur during seawater-adaptation. Most Oreochromis niloticus adapted in seawater had an occasional glomerulus completely filling Bowman's capsule in kidney, and glomerular shrinkage was occurred higher in kidney tissues of individuals living in 10%o, 20%o, 30%o of seawater than in those living in 0%o of freshwater, and blood congestion was occurred severer in kidney tissues of individuals living 20%o, 30%o of seawater than in those living in 10%o of seawater. There were decreases in the glomerular area and the nuclear area in the main segments of the nephron, and that the nuclear areas of the nephron cells in seawater-adapted tilapia were of smaller size than those from freshwater-adapted fish. Our findings demonstrated that Oreochromis niloticus tolerated moderately saline environment and the increased body weight living in 30%o was relatively higher than that living in 10%o in spite of histopathological changes.

• Childhood Kidney Diseases
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• v.14 no.2
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• pp.143-153
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• 2010

Purpose: Recently, massive proteinuria has been observed in some transplant patients after switching cyclosporine A (CsA) to sirolimus. To evaluate the pathogenesis of sirolimus-associated proteinuria, we investigated the early changes in slit diaphragm molecules by various administrative conditions of sirolimus and CsA. Methods: In vitro-Mouse podocytes were incubated with buffer (C), sirolimus ($10\;{\mu}g/mL$) after CsA ($10\;{\mu}g/mL$) (C-S), sirolimus only (S) and CsA and sirolimus simultaneously (C+S) for 12, 24, and 48 hours. In vivo- twenty four SPF female Wistar rats were divided into 4 groups buffer (C), sirolimus after 2 weeks of CsA (C-S), sirolimus only (S) and CsA and sirolimus simultaneously (C+S). All groups were treated by intraperitoneal injection every other day for 4 weeks (CsA: 25 mg/kg, sirolimus: 0.5 mg/kg). The changes in mRNA of slit diaphragm molecules were examined by RT-PCR. Results: The mRNA of nephrin was significantly decreased in group C-S and C+S in vitro. In vivo, the mRNA of nephrin in all groups using sirolimus and the mRNA of podocin in group C-S and C+S were decreased. Microscopically, group C-S and C+S showed small vacuolization and calcification in proximal tubular epithelial cells. Immunohistochemistry using nephrin and podocin antibodies did not show remarkable decrease of staining along the glomerular capillaries. Electron-microscopically, focal fusion of foot processes was seen in group C-S and C+S. Conclusion: This study suggests the decrease of slit diaphragm molecules (nephrin and podocin) in podocyte may be one of the causes of sirolimus associated proteinuria, and podocyte injury by sirolimus may need a primary hit by CsA to develop the proteinuria.

• Applied Microscopy
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• v.38 no.2
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• pp.141-148
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• 2008

Nitric oxide (NO) is an important regulator of renal blood flow, glomerular hemodynamics, and tubule transport processes in the kidney. There is also evidence that NO is involved in cell cycle regulation and mitotic division. During development the nNOS expression pattern differs from that observed in adult animals. However, little is known about temporal and spatial patterns of nNOS expression in the developing kidney. The purpose of this study was to establish the time of expression and the distribution of nNOS in the developing rat kidney. Kidneys from 14-, 16-, 17-, 18-, and 20-day-old fetuses, 1-, 4-, 7-, 14-, and 21-day-old pups, and adult animals were preserved and processed for immunohistochemistry. In the adult kidney, nNOS was detected in the parietal epithelium of Bowman s capsule, macula densa, descending thin limb and inner medullary collecting duct. nNOS immunoreactivity appeared first in the distal tubule anlage at 15 days of gestation, and in all epithelial cells of developing thick ascending limbs (TAL) as well as macula densa of 17- and 18-day-old fetuses. From 20 days of gestation to 14 days after birth, nNOS was expressed in the newly formed cortical TAL, which are located in the medullary ray, whereas in mature TAL of juxtamedullary nephrons, nNOS immunolabeling gradually decreased in intensity and became restricted to the macula densa. In inner medullary collecting ducts, nNOS immunoreactivity appeared first at 7 days after birth in the papillary tip and gradually ascended to the border between outer and inner medulla. In the descending thin limb and parietal epithelium of Bowman's capsule, weak nNOS immunoreactivity was observed at 14 days after birth and labeling gradually increased to adult levels at 21 days after birth. These results suggest that differential expression of nNOS in the developing kidney is an important physiological regulator of renal function during kidney maturation.