Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Urologi och njurmedicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Urology and Nephrology (hsv//eng)

Nyckelord

Actins/genetics

Angiotensin II Type 1 Receptor Blockers

Animals

Animals

Newborn

Antihypertensive Agents/*pharmacology

Apoptosis/drug effects

Arachidonate 12-Lipoxygenase/genetics

Cell Communication/*drug effects

Cell Division/drug effects

Extracellular Matrix/drug effects

Gene Expression/drug effects

Histocompatibility Antigens Class II/genetics

Integrin alpha3/genetics

Integrin alpha6/genetics

Kidney/drug effects/*growth & development/*pathology

Losartan/*pharmacology

Membrane Glycoproteins/genetics

Oligonucleotide Array Sequence Analysis

Proteoglycans/genetics

Rats

Rats

Wistar

Syndecan-2

Newborn

MEDICINE

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)