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.

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,~30% of which encode various components of cytoskeleton and cytoskeletonassociated 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, ␣-smooth muscle actin, MHC class II, and leukocyte type 12-lipoxygenase by day 4. In addition, losartan inhibited medullary expression of integrin ␣6 and caused relocalization of integrins ␣6 and ␣3. 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 ␣-smooth muscle actin by the renin-angiotensin system in the immature kidney adds new knowledge toward the understanding of renal vascular development.Renal maldevelopment in premature infants and infants who are small for gestational age is known to be related to hypertension in adult life (1) and may be attributed to the suppressed intrarenal renin-angiotensin system (RAS) in neonates (2). In humans, nephrogenesis is completed before gestational week 36, whereas, in rodents, nephrogenesis is not completed until 10 d after birth (3). Thus, rats and mice are born with immature kidneys, and the first 2 postnatal weeks correspond approximately to the second and third trimesters in humans. This difference provides a convenient animal model for studying mechanisms underlying the RAS-mediated kidney development in human fetus.The importance of the RAS for normal kidney development has been demonstrated by a number of studies using gene targeting or pharmacologic interruption of the RAS (4). Thus, inhibition of angiotensin-converting enzyme activity or angiotensin II type 1 receptor (AT 1 ) but not AT 2 signaling in animals with an ongoing nephrogenesis induces kidney abnormalities (5). The most pronounced structural change is papillary atrophy, and it is associated with impaired urinary concentrating ability (5). Kidney vasculature is also affected, characterized by fewer, thicker, and shorter afferent arterioles (6).Despite the well-recognized renal abnormalities after neonatal RAS inhibition, little is known about mechanisms by which...

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.

Neonatal ACE inhibition in rats interferes with lung development.Lasaitiene, Daina; Chen, Yun; Nannmark, Ulf; Wollmer, Per; Friberg, Peter Link to publication Citation for published version (APA): Lasaitiene, D., Chen, Y., Nannmark, U., Wollmer, P., & Friberg, P. (2004). Neonatal ACE inhibition in rats interferes with lung development. Clinical Physiology and Functional Imaging, 24(1), 65-68. DOI: 10.1046/j.1475-0961.2003 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Neonatal ACE inhibition in rats interferes with lung development Key wordsangiotensin-converting enzyme; lung development; renin-angiotensin system; surface tension; Wilhelmy balance SummaryThe 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.

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.