Nephrogenesis and angiotensin II receptor subtypes gene expression in the fetal lamb

Abstract

To investigate the role of angiotensin II (ANG II) in nephrogenesis, a developmental study of renal AT1 and AT2 receptor mRNA expression was performed in parallel with the quantitative and qualitative analysis of metanephros development in fetal lamb from 60 to 140 days of gestation. Both ANG II receptor subtypes were expressed early during nephrogenesis but displayed specific spatial and temporal distribution during gestation. High-AT2 mRNA expression took place in the outermost nephrogenic area and in the undifferentiated mesenchymal cells surrounding the ampulla; level of AT2 expression in this localization followed closely glomeruli proliferation rate and disappeared after nephrogenesis completion (>120 days). AT2 mRNA was also detected in the differentiated epithelial cells of macula densa of maturing glomeruli. Although most of AT1 mRNA labeling was found in the mesangial cells of maturing glomeruli, where it persisted after nephrogenesis completion, additional labeling was found in undifferentiated cells, in cells invading the inferior cleft of S-shaped bodies (80 days), and in medullar cells between tubules (120 days). Our results suggest that each receptor subtype has a specific role in renal morphogenesis, i.e., AT2 in mesenchymal proliferation or apoptosis and AT1 in vascular smooth muscle cells differentiation.

Renal growth retardation following angiotensin II type 1 (AT1) receptor antagonism is associated with increased AT2 receptor protein in fetal sheep

“…Fractional glomerular volume is an estimation of total filtration capacity, taking into consideration both glomerular number and volume. Nephron number was not determined in this study, although nephrogenesis in the sheep fetus is near completion at 130 days of gestation (Gimonet et al 1998). These findings confirm those observed in rats where administration of the AT 1 -specific receptor antagonist, losartan, in the first 3 weeks of postnatal life causes a decrease in the absolute and relative size of the kidney (Tufro-McReddie et al 1994).…”

“…Previous studies in fetal sheep have demonstrated that there are only mature glomeruli present in the developing kidney from 120 days of gestation (Gimonet et al 1998). In this study at 130 days of gestation, all the glomeruli were mature and were identified with a clearly defined capsule and capillary structure.…”

“…Finally, AT 1 receptor blockade in utero may delay the normal developmental reduction in renal AT 2 receptor protein expression. In fetal ovine kidneys, AT 2 receptor gene expression decreases during late gestation to an undetectable level by term (Butkus et al 1997, Gimonet et al 1998. This developmental decline in AT 2 receptor expression may depend on AT 1 receptor activity, although AII receptor subtype levels were not determined at the gestational age at the start of the infusion in this study.…”

“…The AT 2 receptor is widely expressed in fetal tissues and, in particular, contributes to the regulation of cell proliferation, differentiation and apoptosis (Nakajima et al 1995, Yamada et al 1996, Nishimura et al 1999, Johren et al 2004. At the gestational age investigated in this study, the AT 2 receptor is localised to the macula densa and interstitial cells of the cortex and medulla in the developing ovine kidney (Butkus et al 1997, Gimonet et al 1998. Therefore, in the GR-treated fetuses, the reduction in kidney size without any change in fractional or mean glomerular volume may have resulted from the anti-proliferative effects of AT 2 receptor stimulation on renal interstitial cells.…”

The renin-angiotensin system in the year 2000

“…It also seems likely that the AT 2 receptor is involved in the development of the kidney and urinary tract. [73][74][75] The ACE gene is very widely expressed, perhaps ubiquitously, through the body. 76 While the primary sites of production of renin and of angiotensinogen are respectively kidney and liver, renin and angiotensinogen genes are extensively manifested in other tissues, many of which, as was stated in the preceding section, have been shown to contain renin.…”