| 1. |
- Burlaka, Ievgeniia, et al.
(författare)
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Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease
- 2016
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Ingår i: Kidney International. - : Nature Publishing Group. - 0085-2538 .- 1523-1755. ; 90:1, s. 135-148
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Tidskriftsartikel (refereegranskat)abstract
- There is a great need for treatment that arrests progression of chronic kidney disease. Increased albumin in urine leads to apoptosis and fibrosis of podocytes and tubular cells and is a major cause of functional deterioration. There have been many attempts to target fibrosis, but because of the lack of appropriate agents, few have targeted apoptosis. Our group has described an ouabain-activated Na,K-ATPase/IP3R signalosome, which protects from apoptosis. Here we show that albumin uptake in primary rat renal epithelial cells is accompanied by a time-and dose-dependent mitochondrial accumulation of the apoptotic factor Bax, down-regulation of the antiapoptotic factor Bcl-xL and mitochondrial membrane depolarization. Ouabain opposes these effects and protects from apoptosis in albumin-exposed proximal tubule cells and podocytes. The efficacy of ouabain as an antiapoptotic and kidney-protective therapeutic tool was then tested in rats with passive Heymann nephritis, a model of proteinuric chronic kidney disease. Chronic ouabain treatment preserved renal function, protected from renal cortical apoptosis, up-regulated Bax, down-regulated Bcl-xL, and rescued from glomerular tubular disconnection and podocyte loss. Thus we have identified a novel clinically feasible therapeutic tool, which has the potential to protect from apoptosis and rescue from loss of functional tissue in chronic proteinuric kidney disease.
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| 2. |
- Chang, Ya-Ting, et al.
(författare)
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Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia
- 2012
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Ingår i: American Journal of Physiology - Lung cellular and Molecular Physiology. - : American Physiological Society. - 1040-0605 .- 1522-1504. ; 302:11, s. L1159-L1166
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-beta were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR-alpha remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed.
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| 3. |
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| 4. |
- Li, Juan, et al.
(författare)
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Ouabain protects against adverse developmental programming of the kidney
- 2010
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 1, s. 42-
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Tidskriftsartikel (refereegranskat)abstract
- The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards the formation of functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that ouabain, the Na, K-ATPase ligand, triggers a calcium-nuclear factor-kappa B signal, which protects kidney development from adverse effects of malnutrition. To mimic malnutrition, kidneys were serum deprived for 24 h. This resulted in severe retardation of nephron formation and a robust increase in apoptosis. In ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given a low-protein diet and treated with ouabain or vehicle throughout pregnancy. Thus, we have identified a survival signal and a feasible therapeutic tool to prevent adverse programming of kidney development.
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| 5. |
- Ringman, Andreas, et al.
(författare)
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NKCC-1 and ENaC are down-regulated in nitrofen-induced hypoplastic lungs with congenital diaphragmatic hernia
- 2008
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Ingår i: Pediatric surgery international (Print). - : Springer Science and Business Media LLC. - 0179-0358 .- 1437-9813. ; 24:9, s. 993-1000
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Tidskriftsartikel (refereegranskat)abstract
- Congenital diaphragmatic hernia (CDH) is accompanied by pulmonary hypoplasia and pulmonary hypertension. Fetal lung growth is dependent on the secretion of lung liquid, which normally is absorbed at partus. The ion channel NKCC-1 is involved in this secretory process, but has recently also been reported to be implicated in absorption. CDH patients show a disturbed transition from secretion to absorption. alpha- and beta-ENaC are essential for lung liquid absorption. Common for all transcellular ion transport is the need for Na/K-ATPase as a primary driving force. The aim of the study was first to map the normal pulmonary expression of the above proteins during late gestation and secondly to see if the expression was affected in a CDH rat model. Pregnant Sprague-Dawley rat dams were given nitrofen on gestational day 9.5 to induce CDH. The fetuses were removed on gestational days E18 and E21. In addition, newborn rats were harvested postpartum on day P2. The fetuses were put into one of two groups: hypoplastic lungs without CDH (N-CDH) and hypoplastic lungs with CDH (N+CDH). The pulmonary expression of NKCC-1, alpha-/beta-ENaC and Na/K-ATPase was then analyzed using Western blot. We found that the protein levels of NKCC-1 on gestational days E18 and E21 were significantly lower among fetuses with N+CDH as well as N-CDH compared to controls. The expression of beta-ENaC was also significantly down-regulated in both the groups on E18 and E21. The protein levels of alpha-ENaC and Na/K-ATPase were not found to be significantly decreased, but both showed a tendency towards down-regulation. The marked down-regulation of NKCC-1 in fetal hypoplastic lungs with CDH indicates a possibly decreased lung liquid production. This may be one of the mechanisms behind the disturbed pulmonary development in CDH. We also show that beta-ENaC is down-regulated. Down-regulation of beta-ENaC may result in abnormal lung liquid absorption, which could be one of the mechanisms behind the respiratory distress seen in CDH patients postpartum.
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| 6. |
- Uggla, Andreas Ringman, et al.
(författare)
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Expression of chloride channels in trachea-occluded hyperplastic lungs and nitrofen-induced hypoplastic lungs in rats
- 2009
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Ingår i: Pediatric surgery international (Print). - : Springer Science and Business Media LLC. - 0179-0358 .- 1437-9813. ; 25:9, s. 799-806
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Tidskriftsartikel (refereegranskat)abstract
- Congenital diaphragmatic hernia is accompanied by pulmonary hypoplasia. Fetal lung growth is dependent on the secretion of lung liquid, in which Cl- secretion by the pulmonary epithelium plays a crucial role. A decrease of lung liquid production during fetal development renders marked pulmonary hypoplasia, while accelerated fetal lung growth in the form of pulmonary hyperplasia can be achieved by in utero tracheal occlusion (TO). Cl- secretion presumably involves NKCC-1, the primary basolateral Cl- entry pathway in airway epithelia, coupled to an apical Cl- exit pathway. The chloride channels ClC-2, -3 and -5, members of the CLC gene family, are all localized to the apical membrane of fetal respiratory epithelia, which makes them possible candidates for being mediators of fetal apical Cl- secretion. The aim of the study was to examine the potential of ClC-2, -3 and -5 as alternative apical airway epithelial Cl- channels in normal lung development and their possible role in the development of hypoplastic lungs in CDH. We also wanted to examine ClC-2, -3 and -5 together with the NKCC-1 in hyperplastic lungs created by TO. Pregnant Sprague-Dawley rat dams were given nitrofen on gestational day 9.5 to induce pulmonary hypoplasia. Controls were given only olive oil. The rat fetuses were removed on days 17, 19 and 21. Hyperplastic lungs were created by intrauterine TO of rat fetuses on day 19 and the lungs were harvested on day 21. The pulmonary expression of ClC-2, -3, -5 and NKCC-1 was then analyzed using Western blot. We found that the temporal expression of ClC-2 and -3 in normal fetal lungs points toward a developmental regulation. ClC-2 and -3 were also both down-regulated on day 21 in hypoplastic CDH lungs. In TO induced hyperplastic lungs, the levels of ClC-2 were found to be significantly up-regulated. NKCC-1 showed a tendency toward up-regulation in hyperplastic lungs, while ClC-3 showed a tendency to be down-regulated, but no statistically significant changes could be seen. There was no difference between controls and any of the groups for the expression of ClC-5. We show that the developmental changes in ClC-2 and ClC-3 protein expression are negatively affected in hypoplastic CDH lungs. Lung hyperplasia created by TO up-regulates the expression of ClC-2. ClC-2 is therefore an interesting potential target in the development of novel, non-invasive, therapies for CDH treatment.
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| 7. |
- Ågren, Johan, et al.
(författare)
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Transepidermal water loss in developing rats : Role of aquaporins in the immature skin
- 2003
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Ingår i: Pediatric Research. - 0031-3998 .- 1530-0447. ; 53:4, s. 558-565
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Tidskriftsartikel (refereegranskat)abstract
- In the extremely preterm infant, high transepidermal water loss (TEWL) can result in severe dehydration. TEWL has been attributed to the structural properties of the epidermis but might also be influenced by mechanisms that facilitate water transport. To investigate whether aquaporins (AQP) may be involved in the extreme losses of water through immature skin, we examined the presence and cellular distributions of AQP-1 and AQP-3 in embryonic and adult rat skin by immunohistochemistry. The expression of AQP mRNA in skin was analyzed with the use of semiquantitative reverse transcription-PCR. In rat pups of different embryonic (E) and postnatal (P) ages (days), TEWL and skin hydration were measured. AQP-1 was detected in dermal capillaries, and AQP-3 was abundant in basal epidermal layers. Both AQP displayed several times higher expression in embryonic than in adult skin. TEWL was highest at embryonic day 18 (E18) (133 +/- 18 g/m2h) and lower at E20 (25 +/- 1 g/m2h) and P4 (9 +/- 2 g/m2h). Skin hydration measured as skin electrical capacitance paralleled TEWL, being highest in fetal skin (794 +/- 15 pF at E18) and decreasing to 109 +/- 11 pF at E20 and to 0 +/- 0 pF at P4. We conclude that, as in infants, water loss through the skin of rats decreases markedly with maturation during the perinatal period. The expression and cellular localization of the AQP are such that they might influence skin hydration and water transport and contribute to the high losses of water through the immature skin.
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