Perturbed medullary tubulogenesis in neonatal rat exposed to renin-angiotensin system inhibition.
BACKGROUND
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.


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-alpha (TNF-alpha) 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-alpha 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-alpha.
Lasaitiene
Daina
D
Department of Physiology, Institute of Physiology and Pharmacology, University of Gothenburg, Box 432, S-405 30 Gothenburg, Sweden. daina.lasaitiene@fysiologi.gu.se
Chen
Yun
Y
Guron
Gregor
G
Marcussen
Niels
N
Tarkowski
Andrzej
A
Telemo
Esbjorn
E
Friberg
Peter
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000096:biosynthesis; D004656:Enalapril / Q000009:adverse effects*; D005260:Female; D007679:Kidney Medulla / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D007684:Kidney Tubules / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014564:Urogenital Abnormalities / Q000139:chemically induced / Q000196:embryology* / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D015820:Cadherins; D014409:Tumor Necrosis Factor-alpha; D004656:Enalapril