| 1. |
- Chen, Yun, 1966, et al.
(författare)
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Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions
- 2004
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Ingår i: Journal of the American Society of Nephrology. - : Lippincott Williams & Wilkins. - 1046-6673 .- 1533-3450. ; 15:5, s. 1232-43
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Tidskriftsartikel (refereegranskat)abstract
- Lack of neonatal angiotensin II type 1 receptor (AT(1)) stimulation produces renal abnormalities characterized by papillary atrophy and impaired urinary concentrating ability, but the mechanisms involved are still unclear. DNA microarray was used to identify genes that are differentially expressed in renal medulla in response to neonatal treatment with AT(1) receptor antagonist losartan (30 mg/kg per d), which commenced within 24 h after birth. The data showed that losartan treatment for 48 h downregulated 68 genes, approximately 30% of which encode various components of cytoskeleton and cytoskeleton-associated proteins, extracellular matrix, and enzymes involved in extracellular matrix maturation or turnover. With the use of immunohistochemistry and Western immunoblot, the microarray data were confirmed and it was demonstrated that losartan suppressed renal expression of syndecan 2, alpha-smooth muscle actin, MHC class II, and leukocyte type 12-lipoxygenase by day 4. In addition, losartan inhibited medullary expression of integrin alpha6 and caused relocalization of integrins alpha6 and alpha3. Moreover, losartan inhibited cell proliferation in medullary tubules by day 9, as detected by Ki-67 immunostaining. This study provides new data supporting the contention that a lack of AT(1) receptor stimulation results in abnormal matrix assembly, disturbed cell-cell and cell-matrix interactions, and subsequent abnormal tubular maturation. Moreover, regulation of the expression of leukocyte type 12-lipoxygenase and alpha-smooth muscle actin by the renin-angiotensin system in the immature kidney adds new knowledge toward the understanding of renal vascular development.
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| 2. |
- Chen, Yun, 1966, et al.
(författare)
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The renin-angiotensin system in kidney development
- 2004
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Ingår i: Acta Physiol Scand. - 0001-6772. ; 181:4, s. 529-35
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Tidskriftsartikel (refereegranskat)abstract
- All components of the renin-angiotensin system (RAS) are highly expressed in the developing kidney in a pattern suggesting a role for angiotensin II in renal development. In support of this notion, pharmacological interruption of angiotensin II type-1 (AT(1)) receptor signalling in animals with an ongoing nephrogenesis produces specific renal abnormalities characterized by papillary atrophy, abnormal wall thickening of intrarenal arterioles, tubular atrophy associated with expansion of the interstitium, and a marked impairment in urinary concentrating ability. Similar changes in renal morphology and function develop also in mice with targeted inactivation of genes encoding renin, angiotensinogen, angiotensin-converting enzyme, or both AT(1) receptor isoforms simultaneously. Taken together, these results clearly indicate that an intact signalling through AT(1) receptors is a prerequisite for normal renal development. The present report mainly reviews the renal abnormalities induced by blocking the RAS pharmacologically in experimental animal models. In addition, pathogenetic mechanisms are discussed.
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| 3. |
- Lasaitiene, Daina, 1970, et al.
(författare)
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Further insights into the role of angiotensin II in kidney development
- 2006
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Ingår i: Clin Physiol Funct Imaging. - 1475-0961. ; 26:4, s. 197-204
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Tidskriftsartikel (refereegranskat)abstract
- Over the past decade, compelling studies have highlighted the fundamental role of the renin-angiotensin system (RAS) in renal development and long-term control of renal function and arterial pressure. The present review provides an update of the understanding of how the RAS controls nephrogenesis and nephrovascular development. In addition, the investigations linking the perinatal development of RAS inhibition-induced renal dysmorphology and establishment of adult blood pressure are discussed.
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| 4. |
- Lasaitiene, Daina, 1970, et al.
(författare)
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Neonatal ACE inhibition in rats interferes with lung development
- 2004
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Ingår i: Clin Physiol Funct Imaging. - : Wiley. - 1475-0961 .- 1475-097X. ; 24:1, s. 65-8
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Tidskriftsartikel (refereegranskat)abstract
- The renin-angiotensin system (RAS) is developmentally up-regulated and it is essential for kidney development in several species. Given the fact that the rat lung undergoes postnatal development, the mammalian lung possesses the highest angiotensin-converting enzyme (ACE) levels and ACE activity increases during the first weeks postpartum, we tested the hypothesis that ACE inhibition influences postnatal lung development. Rats were given the ACE inhibitor enalapril (10 mg kg(-1)) from 0 to 9 days of age and their lungs were examined at day 4 and 9. Lung structure was evaluated by means of light microscopy, and surface tension of bronchoalveolar lavage fluid was measured by means of a Wilhelmy balance. Neonatal ACE inhibition lowered the surface tension of bronchoalveolar lavage fluid and caused widening of respiratory airspaces and thinning of alveolar septa. Our results suggest that early postnatal ACE inhibition in rats interferes with lung development.
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| 5. |
- Lasaitiene, Daina, 1970, et al.
(författare)
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Neonatal RAS inhibition changes the phenotype of the developing thick ascending limb of Henle
- 2004
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Ingår i: Am J Physiol Renal Physiol. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 286:6
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological interruption of angiotensin II type 1 (AT(1)) receptor signaling during nephrogenesis in rats perturbs renal tubular development. Perturbed tubulogenesis may contribute to long-term impairment of urinary concentrating ability, which is the main functional irreversible defect. The aim of this study was to further characterize tubular developmental deficits in neonatal rats, focusing on the thick ascending limb of Henle (TALH), known to undergo profound developmental changes and to be involved in urine-concentrating mechanisms. We have carried out immunohistochemistry and Western immunoblotting using antibodies directed against the major histocompatibility complex class II (MHC II) molecule and different TALH-specific markers, namely, cyclooxygenase-2 (COX-2), Tamm-Horsfall glycoprotein (THP), and the bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter (BSC-1/NKCC2). Immunohistochemistry demonstrated expression of MHC II, COX-2, THP, and BSC-1/NKCC2 proteins in normally developing TALH cells. The AT(1)-receptor antagonist losartan abolished MHC II expression exclusively in the developing TALH cells. Increased expression of COX-2 and THP was observed in the TALH cells of losartan-treated rats. Western immunoblotting confirmed increases in cortical and medullary COX-2 and THP abundance and revealed a decrease in cortical BSC-1/NKCC2 abundance in response to losartan treatment. We conclude that neonatal losartan treatment causes significant changes in the phenotype of the developing TALH in the rat.
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| 6. |
- Lasaitiene, Daina, 1970, et al.
(författare)
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Perturbed medullary tubulogenesis in neonatal rat exposed to renin-angiotensin system inhibition.
- 2003
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Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - 0931-0509. ; 18:12, s. 2534-41
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological interruption of the angiotensin II type-1 receptor (AT(1)) signalling during nephrogenesis in rats induces irreversible abnormalities in kidney morphology, comprising papillary atrophy and tubulointerstitial damage, which are characterized by tubular dilatation/atrophy and interstitial inflammation/fibrosis. This study determined the time course for development of tubular structural and inflammatory changes and possible cytokine production in the renal medulla of newborn rats exposed to angiotensin-converting enzyme (ACE) inhibition. Additionally, medullary expression of E-cadherin, a marker for tubular formation, was investigated in ACE-inhibited rats.
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| 7. |
- Lasaitiene, Daina, 1970
(författare)
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The renin-angiotensin system in renal tubulogenesis. Experimental studies in the rat
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The kidney and the renin-angiotensin system (RAS) are vital regulators of blood pressure and salt-water balance. In order to appropriately regulate circulatory homeostasis, the kidney must undergo normal development, in which the RAS plays a crucial role. The main effector peptide of the RAS is angiotensin II (ANG II), which governs mammalian nephrogenesis predominantly through stimulation of ANG II type 1 (AT1) receptors. Perinatal lack of AT1 receptor stimulation leads to long-term renal damage that is characterized by tubulointerstitial inflammation/fibrosis, papillary atrophy and renal vascular changes. Irreversible morphologic abnormalities are associated with a pronounced disability in urine concentration. The inadvertent use of angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor blockers in pregnant women causes neonatal oliguria and renal tubular dysplasia. These findings highlight the pivotal role of the RAS in human nephrogenesis. Generally, the present study attempted to construct the sequence of early morphologic-mechanistic events in the developing kidney of the rat subjected to neonatal pharmacologic blockade of the RAS, focusing on the role of the RAS in tubulogenesis. Specifically, this study: 1) determined the time course of tubular structural and inflammatory changes in the developing renal medulla; 2) identified genes involved in the RAS-mediated developmental process of the renal medulla; 3) characterized developmental defects of the thick ascending limb of Henle (TALH); and 4) characterized developmental defects of the tubules at a subcellular level. The following methods were employed in the present study: light and electron microscopy; stereological analysis; DNA microarrays, Western blotting and immunohistochemistry; flow cytometry and spectrophotometric analysis. The present study demonstrated that pharmacologic interruption of AT1 receptor signaling in the newborn rat induces irreversible medullary tubular changes, firstly, and triggers an inflammatory response, secondly. Perturbed tubulogenesis is associated with, and may partly result from, alterations in the assembly of extracellular matrix and nephrovascular development. Neonatal lack of ANG II stimulation causes phenotypic changes in the developing TALH. Developmental defects in the TALH provide an explanatory support for the reduced sodium reabsorption and disability to concentrate urine in adult rats subjected to neonatal inhibition of the RAS. Furthermore, early structural and functional changes in the mitochondria of the developing tubular cells devoid of ANG II stimulation provide the propensity for the tubular developmental defect. Altogether, this thesis presents an advanced pathogenetic insight into the RAS-mediated renal tubulogenesis in the rat.
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| 8. |
- Lasaitiene, Daina, 1970, et al.
(författare)
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Tubular mitochondrial alterations in neonatal rats subjected to RAS inhibition.
- 2006
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Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 290:5
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological interruption of the angiotensin II (ANG II) type 1 receptor signaling during nephrogenesis in rats perturbs renal tubular development. This study aimed to further investigate tubular developmental defects in neonatal rats subjected to ANG II inhibition with enalapril. We evaluated tubular ultrastructural changes using electron microscopy and estimated spectrophotometrically activity or concentrations of succinate dehydrogenase (SDH), cytochromes a and c, which are components of mitochondrial respiratory chain, on postnatal days 2 and 9 (PD2 and PD9). Renal expression of sodium-potassium adenosinetriphosphatase (Na(+)-K(+)-ATPase) and two reflectors of mitochondrial biogenesis [mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20)] also were studied using Western immunoblotting and immunohistochemistry. Enalapril disrupted inner mitochondrial membranes of developing cortical and medullary tubular cells on PD2 and PD9. These findings were paralleled by impaired mitochondrial respiratory function, as revealed from the changes in components of the mitochondrial respiratory chain, such as decreased cytochrome c level in the cortex and medulla on PD2 and PD9, decreased cytochrome a level in the cortex and medulla on PD2, and diminished cortical SDH activity on PD2 and PD9. Moreover, tubular expression of the most active energy-consuming pump Na(+)-K(+)-ATPase was decreased by enalapril treatment. Renal expression of TFAM and TOM20 was not altered by neonatal enalapril treatment. Because nephrogenesis is a highly energy-demanding biological process, with the energy being utilized for renal growth and transport activities, the structural-functional alterations of the mitochondria induced by neonatal enalapril treatment may provide the propensity for the tubular developmental defect.
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| 9. |
- Nilsson, Annika B M, et al.
(författare)
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Growth hormone aggravates renal abnormalities induced by neonatal enalapril treatment.
- 2003
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Ingår i: Pediatric nephrology (Berlin, Germany). - : Springer Science and Business Media LLC. - 0931-041X .- 1432-198X. ; 18:9, s. 878-86
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Tidskriftsartikel (refereegranskat)abstract
- Lack of neonatal angiotensin II type-1 receptor stimulation produces irreversible abnormalities of renal function and morphology, which can be prevented by simultaneous administration of insulin-like growth factor-I (IGF-I). Given the fact that growth hormone (GH) is the strongest secretagogue for IGF-I, we wanted to explore whether GH could reproduce the effect of IGF-I. Rats were treated from 3 to 13 days of age with the angiotensin-converting enzyme inhibitor enalapril (10 mg/kg/day) and GH (4 mg/kg/day), alone or in combination. Renal gene expression of IGF-I and IGF-binding proteins (IGFBP) was determined during and after treatment. Renal function and morphology were investigated at adult age. In contrast to the beneficial effect of IGF-I, GH treatment in combination with enalapril further deteriorated both renal function and morphology as compared with enalapril treatment alone, demonstrating: reduced glomerular filtration rate, increased tubular dilation and further expansion of the outer medulla. Enalapril decreased medullary expression of IGF-I and increased renal expression of IGFBP-1, changes that were not affected by concomitant GH treatment. These findings indicate that GH and IGF-I have different roles in the renin-angiotensin system-mediated kidney development.
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