Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions
Journal article, 2004
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.
Newborn
Oligonucleotide Array Sequence Analysis
Cell Division/drug effects
Rats
Losartan/*pharmacology
Histocompatibility Antigens Class II/genetics
Cell Communication/*drug effects
Syndecan-2
Antihypertensive Agents/*pharmacology
Kidney/drug effects/*growth & development/*pathology
Wistar
Apoptosis/drug effects
Animals
Proteoglycans/genetics
Animals
Actins/genetics
Angiotensin II Type 1 Receptor Blockers
Membrane Glycoproteins/genetics
Extracellular Matrix/drug effects
Gene Expression/drug effects
Rats
Integrin alpha3/genetics
Integrin alpha6/genetics
Arachidonate 12-Lipoxygenase/genetics
Author
Yun Chen
University of Gothenburg
Daina Lasaitiene
University of Gothenburg
Britt Gabrielsson
University of Gothenburg
Lena M S Carlsson
University of Gothenburg
Håkan Billig
University of Gothenburg
Björn Carlsson
University of Gothenburg
N. Marcussen
X. F. Sun
Peter Friberg
University of Gothenburg
Journal of the American Society of Nephrology : JASN
1046-6673 (ISSN) 1533-3450 (eISSN)
Vol. 15 5 1232-43Subject Categories
Physiology
MEDICAL AND HEALTH SCIENCES
DOI
10.1097/01.ASN.0000123690.75026.3F
PubMed
15100363