Nephrol Dial Transplant (2003) 18: 2534-2541
© 2003 European Renal Association-European Dialysis and Transplant Association
Original Article
Perturbed medullary tubulogenesis in neonatal rat exposed to renin–angiotensin system inhibition
1Department of Physiology, Institute of Physiology and Pharmacology, 2Department of Clinical Physiology, 3Department of Rheumatology and Inflammation Research, University of Gothenburg, Sweden and 4Department of Pathology, University of Aarhus, Denmark
Correspondence and offprint requests to: Daina Lasaitiene, MD, Department of Physiology, Institute of Physiology and Pharmacology, University of Gothenburg, Box 432, S-405 30, Gothenburg, Sweden. Email: daina.lasaitiene{at}fysiologi.gu.se
Background. Pharmacological interruption of the angiotensin II type-1 receptor (AT1) 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.
Methods. Newborn rats were exposed (postnatal days 0–12) to ACE inhibitor enalapril and killed at days 1, 2, 4, 9 and 13. One kidney was used for morphological evaluation and the other for immunohistochemistry, using antibodies directed against monocytes/macrophages, T cells and E-cadherin on frozen sections. In a separate experiment, rats were treated for 9 days and had their kidneys processed for western immunoblot and immunohistochemistry, where antibodies directed against monocyte chemoattractant protein-1 (MCP-1) and tumour necrosis factor-
(TNF-) were used on paraffin sections.
Results. In renal medulla from enalapril-treated rats, volume fractions of tubular lumens and interstitium were increased from postnatal days 2 and 4, respectively, while that of tubular cells was decreased from 4 days of age. Concomitant loss and/or reduction in E-cadherin expression (from day 2) was observed in dilated medullary tubules of enalapril-treated rats. Furthermore, in the medulla of enalapril-treated rats, the increased number of ED2+ (resident macrophages) cells, followed by the increase in ED1+ (monocytes/macrophages) and CD4+ T cells, was observed at days 9 and 13, respectively. This was accompanied by increased medullary expression of TNF- at day 9.
Conclusions. Neonatal ACE inhibition perturbs medullary tubulogenesis, as indicated by tubular dilatation and a lack of E-cadherin expression in these tubules. Macrophage/monocyte-mediated immune response is a secondary event, coincidentally associated with the up-regulation of TNF-.
Keywords: angiotensin-converting enzyme inhibition; E-cadherin; inflammation; renin–angiotensin system; renal development; tubulogenesis
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