Elevated levels of endogenous angiotensin can cause hypertensive nephrosclerosis as a result of the potent vasopressor action of the peptide. We have produced by gene targeting mice homozygous for a null mutation in the angiotensinogen gene (Atg-'-). Postnatally, Atg-'-animals show a modest delay in glomerular maturation. Although Atg-'-animals are hypotensive by 7 wk of age, they develop, by 3 wk of age, pronounced lesions in the renal cortex, similar to those of hypertensive nephrosclerosis. In addition, the papillae of homozygous mutant kidneys are reduced in size. These lesions are accompanied by local up-regulation of PDGF-B and TGF-fi1 mRNA in the cortex and down-regulation of PDGF-A mRNA in the papilla. The study demonstrates an important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney. The mechanism through which angiotensin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla. (J. Clin. Invest. 1995.

The cellular distribution of angiotensin II type 1 (AT1) and type 2 (AT2) receptor mRNA was examined in mouse kidneys at several embryonic stages (12 to 18 days; 19 days = full term) and up to three weeks after birth by in situ hybridization. The expression of both AT1 and AT2 mRNAs appeared simultaneously at 14 days of gestation. However, their distributions were contrasting: AT1 mRNA was expressed in mature glomeruli and maturing S-shaped bodies throughout the stages examined. AT1 expression was also detected at 16 days of gestation in the proximal and distal tubules and peaked at the end of gestation. Both the temporal and spatial expression of AT1 coincide with the differentiation and proliferation of glomerular mesangial and tubular cells during nephrogenesis. In contrast, AT2 mRNA was present only in the mesenchymal cells adjacent to the stalk of the ureter bud at early developmental stages, and, later, extended to the mesenchymal cells located near, but outside, the nephrogenic area of superficial cortex and also the cells between collecting ducts. AT2 expression in these regions decreased markedly within three weeks after birth. Temporally and spatially, AT2 mRNA expression coincides with the epithelial-mesenchymal interactions that take place during early phases of nephrogenesis. The site of AT2 expression also overlaps closely with that of a specific group of cells which undergo apoptosis following nephrogenesis. Thus, contrary to current belief, the activation of AT1 and AT2 genes takes place in different cell types of the kidney during embryonic development, and thereby conceivably contributes to the ontogeny of those specific renal cells.

We have developed chimeric mice carrying 'regional' null mutation of the angiotensin type 1A (AT1A) receptor, the AT1 receptor subtype exclusively present in mouse juxtaglomerular (JG) cells. The chimeric mouse ( Agtr1a Ϫ / Ϫ ↔ ϩ / ϩ ) is made up of wild-type ( Agtr1a ϩ / ϩ ) cells or cells homozygous for Agtr1a deletion (Agtr1a Ϫ / Ϫ ). In the latter, the AT1A coding exon was replaced with a reporter gene,

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