Neonatal Losartan Treatment Suppresses Renal Expression of Molecules Involved in Cell-Cell and Cell-Matrix Interactions

Abstract

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...

Renal function in angiotensinogen gene-mutated renal tubular dysgenesis with glomerular cysts

“…Interestingly, several gene target mouse models, such as AGT and AT1 receptor knock-out mice, have shown a markedly atrophic papilla and dilated pelvis due to polyuria [13,14]. Rat models of ACEI and ARB fetopathy present with papillary atrophy, tubulointerstitial fibrosis, and tubular atrophy and dilation, resulting in impairment of their urinary concentrating ability [15,16]. Renal tubular dysfunction and salt-losing NDI in our patient were compatible with the papillary atrophy observed in animal models.…”

MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams

“…These alterations can progress to the loss of renal function [44]. Chen et al determined that treating rat pups for 2 days with losartan provoked downregulation of genes encoding cytoskeletal and ECM components, resulting in ECM malformation cell-cell and cell-matrix interaction dysfunction [45]. The mechanisms responsible for the increased number of myofibroblasts in the renal cortices of pups born from dams receiving losartan during lactation have not been identified.…”

An insertion/deletion ACE polymorphism and kidney size in Polish full-term newborns

“…1 RAS plays a critical role in kidney development. 11,20 Loss-of-function mutations in the genes encoding components of the RAS or pharmacological inhibition of RAS in animals or humans cause diverse renal malformations, [21][22][23][24][25][26][27][28] including low nephron endowment. 10,29,30 However, the mechanisms by which an intact RAS controls proper renal system development, and how decreased angiotensin II (ANG II) generation or availability results in abnormal kidney development are still not fully elucidated.…”