Foetal kidney maldevelopment in maternal use of angiotensin II type I receptor antagonists

Abstract

We report renal lesions observed in a foetus exposed throughout pregnancy to angiotensin II type I (AT 1) receptor antagonists. The mother suffered from essential hypertension and was treated with Cozaar (losartan 50 mg). Autopsy examination of the foetus revealed severe renal lesions, including tubular dysgenesis, hypertrophy of the endothelial and medial cells lining the arterial and arteriolar walls, hyperplasia of the juxtaglomerular apparatus and poorly developed vasa recta. Similar lesions have already been observed in foetuses of women treated with angiotensin-converting enzyme antagonists and also in foetuses and neonates of animals undergoing experimental blockade of the renin-angiotensin system. The purpose of this report is to describe structural lesions observed in the kidneys, and, particularly, vascular lesions. Our results suggest that the use of AT 1 receptor antagonists during pregnancy may have a severe deleterious effect on kidney development in the foetus.

The role of oxidative stress in renal injury induced in rats by losartan exposure during lactation

“…3 However, the effect of tempol treatment in these animals was limited probably because AII also has several effects that are not mediated by oxidative stress such as the proliferation and differentiation of the tubular, interstitial and vascular cells. 4,5,14,15 It can explain the abnormalities in renal vasculature and tubule interstitial compartment observed in both groups of losartan-treated rats, considering that cell proliferation and differentiation are important events in development.…”

“…1,2 Clinical and experimental evidence indicates that the renin-angiotensin system (RAS) participates in renal development. [3][4][5][6] All RAS components are expressed early at a high intensity in embryogenesis. 7,8 Angiotensin II (AII) stimulates cultured mesangial cells to produce various extracellular matrix (ECM) components 9 and promotes cell proliferation and differentiation.…”

“…5 It was observed that human fetal kidneys from the offspring of mothers that received type 1 AII receptor (AT 1 ) antagonists during gestation have poorly developed tubules, increased renal mesenchymal tissue, decreased numbers of proximal tubules, abnormal arterial and arteriolar walls, and poorly developed vasa recta and hyperplasic juxtaglomerular apparati. 4 The inhibition of the RAS by administering AII antagonists to rats during postnatal development causes abnormalities in renal structure, including reduced glomerular volume, tubular dilation, papillary atrophy and increased interstitial relative area of the renal cortex. 1,3,13,14 These changes lead to a progressive loss of renal function.…”

Development of the kidney medulla

“…Moreover, administration of AT1R antagonist during pregnancy in humans results in atrophy of the renal medulla and poorly developed vasa recta in the fetal kidney. 42 Double-mutant mice deficient in high mobility group (HMG) box transcription factor genes Sox17/Sox18, show reduced neovascularization in the outer medulla vasa recta on postnatal day 7. 43 Notably, AT1R or Sox17 mutations are causative factors in CAKUT in humans.…”

A population-based case control study of congenital abnormalities and medication use during pregnancy using the Czech National Register of congenital abnormalities

“…Well-known drugs which interfere in the development of the kidneys are inhibitors of angiotensin converting enzyme and antagonists of angiotensin II type 1 receptor [7,8]. Undoubtedly, there are more biochemical modulators in this process than the renin-angiotensin system and angiotensin receptor.…”